Secure and Efficacious Therapy Delivery for a Pacing Engine

ABSTRACT

The above-described methods and apparatus are believed to be of particular benefit for patients suffering heart failure including cardiac dysfunction, chronic HF, and the like and all variants as described herein and including those known to those of skill in the art to which the invention is directed. It will understood that the present invention offers the possibility of monitoring and therapy of a wide variety of acute and chronic cardiac dysfunctions. The current invention provides systems and methods for delivering therapy for cardiac hemodynamic dysfunction via the innervated myocardial substrate receives one or more discrete pulses of electrical stimulation during the refractory period of said innervated myocardial substrate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent disclosure is a continuation of co-pending non-provisionalU.S. patent application Ser. No. 10/703,956 entitled, “SECURE ANDEFFICACIOUS THERAPY DELIVERY FOR AN EXTRA-SYSTOLIC STIMULATION PACINGENGINE,” filed November 2003 and issued 19 Jun. 2007 as U.S. Pat. No.7,233,824 the entire contents of which are hereby incorporated byreference herein. This patent disclosure is also a continuation of,relates to and incorporates by reference co-pending non-provisional U.S.patent application Ser. No. 10/638,855 filed 11 Aug. 2003 entitled,“ELECTRICALLY EFFICIENT NEURALLY-EXCITABLE STIMULATION,” and is also acontinuation of non-provisional U.S. patent application Ser. No.11/379,886 filed 24 Apr. 2006, the contents of which are also herebyincorporated herein.

FIELD OF THE INVENTION

hThe present invention relates generally to implantable medical devicesand more specifically to providing appropriate therapies for acute orchronic cardiac mechanical dysfunction such as heart failure (HF),cardiogenic shock, pulseless electrical activity (PEA), orelectromechanical dissociation (EMD).

BACKGROUND OF THE INVENTION

Patients suffering from chronic HF manifest an elevation of leftventricular end-diastolic pressure and frequently volume, according tothe well-known heterometric autoregulation principles espoused by Frankand Starling. This may also occur while left ventricular end-diastolicvolume remains normal due to a decrease in left ventricular complianceconcomitant with increased ventricular wall stiffness. HF due to chronichypertension, ischemia, infarct or idiopathic cardiomyopathy isassociated with compromised systolic and diastolic function involvingdecreased atrial and ventricular muscle compliance. These may beconditions associated with chronic disease processes or complicationsfrom cardiac surgery with or without specific disease processes. Mostheart failure patients do not normally suffer from a defect in theconduction system leading to ventricular bradycardia, but rather sufferfrom symptoms which may include a general weakening of the contractilefunction of the cardiac muscle, attendant enlargement thereof, impairedmyocardial relaxation and depressed ventricular filling characteristicsin the diastolic phase following contraction. Pulmonary edema, shortnessof breath, and disruption in systemic blood pressure are associated withacute exacerbations of heart failure. All these disease processes leadto insufficient cardiac output to sustain mild or moderate levels ofexercise and proper function of other body organs, and progressiveworsening eventually results in cardiogenic shock, arrhythmias,electromechanical dissociation, and death.

Such patients are normally treated with drug therapies, includingdigitalis, which may lead to toxicity or lose effectiveness over time.Many inotropic drugs have recently become available, targeted at variousreceptors in the myocyte and designed for the purpose of directlystimulating cardiac tissue in order to increase contractility. However,there exist many possible undesirable side effects, in addition to thefact that these drugs do not always work for their intended purpose.This is especially characteristic of the patient suffering fromend-stage heart failure.

Since dual chamber pacing was developed, conventional, atrioventricular(AV) synchronous pacing systems, including DDD and DDDR pacing systems,marketed by Medtronic, Inc. and other companies, have also beenprescribed for treatment of HF as well as a variety of bradycardiaconditions. Certain patient groups suffering heart failure symptoms withor without bradycardia tend to do much better hemodynamically with AVsynchronous pacing due to the added contribution of atrial contractionto ventricular filling and subsequent contraction. However, fixed orphysiologic sensor driven rate responsive pacing in such patients doesnot always lead to improvement in cardiac output and alleviation of thesymptoms attendant to such disease processes because it is difficult toassess the degree of compromise of cardiac output caused by HF and todetermine the pacing parameters that are optimal for maximizing cardiacoutput. Selection of an optimal AV delay often requires obtainingpressure data involving an extensive patient work-up as set forth incommonly assigned U.S. Pat. No. 5,626,623.

A series of PCT publications including, for example, PCT WO 97/25098describe the application of one or more “non-excitatory” anodal orcathodal stimulation pulses to the heart and maintain that improvementsin LV performance may be realized without capturing the heart. In afurther commonly assigned U.S. Pat. No. 5,800,464, the contents of whichare hereby incorporated by reference herein, sub-threshold anodalstimulation is provided to the heart to condition the heart tomechanically respond more vigorously to the conventional cathodalsupra-threshold pacing pulses.

Thus, various stimulation regimens have been proposed for the treatmentof cardiac dysfunction including HF which involve application ofsupra-threshold and/or sub-threshold stimulation paired or coupledpacing pulses or pulse trains. Moreover, various electrodes have beenproposed for single site and multi-site delivery of the stimulationpulses to one or more heart chambers in the above-referenced patents andpublications. However, it remains difficult to economically determineappropriate candidates that would benefit from such stimulation and tomeasure the efficacy of a given stimulation regimen and/or electrodearray. Extensive catheterization procedures must be conducted of a heartfailure patient to determine if he or she is a candidate forimplantation of such a system. Then, the efficacy of any given treatmentmust be assessed at implantation and in periodic post-implant follow-upclinical tests. The patient work-up and follow-up testing must take intoaccount or simulate known patient activities, patient posture, andwhether the patient is awake or asleep in order to be representative ofthe heart failure condition over a daily time span. Furthermore, thesetherapies are susceptible to losing efficacy or causing arrhythmias withshifts in stimulation timing or the physiologic response to stimulation.

Physiologic and device operating data gathering capabilities have beenincluded in modern implantable cardiac pacemakers and implantablecardioverter/defibrillators (ICDs) in order to provide a record ofbradycardia or tachyarrhythmia episodes and the response to sameprovided by the pacemaker or ICD. The stored physiologic deviceoperations and patient data as well as real-time electrogram (EGM) datacan be uplink telemetered to an external programmer for display andanalysis by medical heath care providers, as is well known in the art.

In addition, implantable cardiac monitors have been clinically used orproposed for use for monitoring hemodynamic and electrical signals of apatient's heart that do not presently include any stimulationcapabilities, e.g., cardiac pacing or cardioversion/defibrillation. Suchimplantable monitors are implanted in patients to develop data over alonger time period than in the clinical setting that can be retrieved inthe same manner and used to diagnose a cardiac dysfunction, includingHF, that manifests itself sporadically or under certain loads andstresses of daily living.

One such implantable EGM monitor for recording the cardiac electrogramfrom electrodes remote from the heart as disclosed in commonly assignedU.S. Pat. No. 5,331,966 and PCT publication WO 98/02209 is embodied inthe Medtronic® REVEAL® Insertable Loop Recorder having spaced housingEGM electrodes. More elaborate implantable hemodynamic monitors (IHMs)for recording the EGM from electrodes placed in or about the heart andother physiologic sensor derived signals, e.g., one or more of bloodpressure, blood gases, temperature, electrical impedance of the heartand/or chest, and patient activity have also been proposed. TheMedtronic® CHRONICLE® IHM is an example of such a monitor that iscoupled through a lead of the type described in commonly assigned U.S.Pat. No. 5,564,434 having capacitive blood pressure and temperaturesensors as well as EGM sense electrodes. Such implantable monitors whenimplanted in patients suffering from cardiac arrhythmias or heartfailure accumulate date and time stamped data that can be of use indetermining the condition of the heart over an extended period of timeand while the patient is engaged in daily activities.

A HF monitor/stimulator is disclosed in commonly assigned U.S. Pat. No.6,104,949 that senses the trans-thoracic impedance as well as patientposture and provides a record of same to diagnose and assess the degreeand progression of HF. The sensed trans-thoracic impedance is dependenton the blood or fluid content of the lungs and assists in the detectionand quantification of pulmonary edema symptomatic of HF. Trans-thoracicimpedance is affected by posture, i.e. whether the subject is lying downor standing up, and the sensed trans-thoracic impedance is correlated tothe output of the patient posture detector to make a determination ofpresence of and the degree of pulmonary edema for therapy deliveryand/or physiologic data storage decisions.

A monitor/stimulator is disclosed in U.S. Pat. No. 5,417,717, thatmonitors and assesses the level of cardiac function then permits aphysician to arbitrate the therapy mode, if therapy is indicated. Themonitor/stimulator assesses impedance, EGM, and/or pressuremeasurements, and then calculates various cardiac parameters. Theresults of these calculations determine the mode of therapy to bechosen. Therapy may be administered by the device itself or a controlsignal may be telemetered to various peripheral devices aimed atenhancing the heart's function. Alternatively, the device may beprogrammed to monitor and either store or telemeter information withoutdelivering therapy.

Particularly, the implantable monitor/stimulator monitors conventionalparameters of cardiac function and contractile state, including allphases of the cardiac cycle. Thus, assessments of contractile statemeasured include indices of both cardiac relaxation and contraction.Utilizing the dual source ventricular impedance plethysmographytechnique described in U.S. Pat. No. 4,674,518, the monitor/stimulatormonitors cardiac function by assessing hemodynamic changes inventricular filling and ejection or by calculating isovolumic phaseindices by known algorithms. The primary calculations involve: (1) thetime rate of change in pressure or volume, dP/dt or dV/dt, as isovolumicindicators of contractility; (2) ejection fraction as an ejection phaseindex of cardiac function according to the known quotient of strokevolume divided by end diastolic volume; (3) Maximal elastance, E_(M);(4) regression slope through maximal pressure-volume points as a furtherejection phase index of contractility using the method of Sagawa; (5)stroke work according to the known pressure-volume integration; (6) thetime course of minimum (end) diastolic pressure-volume measurementsaccording to the method of Glantz as a measure of diastolic function;and (7) cardiac output calculation according to the known product ofheart rate and stroke volume as an index of level of global function.

While measurement and storage of this group of parameters of cardiacfunction and contractile state can provide valuable information aboutthe state of heart failure, there are other parameters that of evengreater value. Momentary changes to a patient's autonomic state canchange blood pressure (P), heart rate, and pressure rate of change(dP/dt) contractility measures and not be reflective of a “true”functional state change of the heart. Such momentary changes inautonomic state are caused by excitement and postural changes as notedin the above-referenced '949 patent and other movements, such as bendingdown to pick up an object or suddenly standing up from a sitting orreclining position. It would be desirable to obtain cardiac data thatprovides an enhanced assessment of cardiac contractile dysfunction state(rather than a measure of pulmonary edema as in the '949 patent) thatare less sensitive to such patient mental states, movements and posturechanges by enhanced signal processing of relatively simple to measurecardiac signals and states.

Preferably, the parameter data is associated with a date and time stampand with other patient data, e.g., patient activity level, and theassociated parameter data is stored in implantable medical device (IMD)memory for retrieval at a later date employing conventional telemetrysystems. Incremental changes in the parameter data over time, taking anyassociated time of day and patient data into account, provide a measureof the degree of change in the condition of the heart.

BACKGROUND OF THE INVENTION

Millions of patients in the U.S. have been diagnosed with heart failure.Heart failure (HF) is not a specific disease, but rather a compilationof signs and symptoms, all of which are caused by an inability of theheart to appropriately increase cardiac output during exertion. HF maybe caused by chronic hypertension, ischemia, tachyarrhythmias, infarctor idiopathic cardiomyopathy. The cardiac diseases associated withsymptoms of congestive failure include dilated cardiomyopathy,restrictive/constrictive cardiomyopathy, and hypertrophiccardiomyopathy. The classical symptoms of the disease include shortnessof breath, edema, and overwhelming fatigue. As the disease progresses,the lack of cardiac output may contribute to the failure of other bodyorgans, leading to cardiogenic shock, arrhythmias, electromechanicaldissociation, and death.

Delivering pacing during the refractory period is a type ofnon-excitatory stimulation (NES) that causes the release ofcatecholamines such as norepinephrine within the tissue of the heart.This chemical release results in an increased contractility of thecardiac tissue, which in turn, results in increased cardiac output,fewer symptoms of heart failure and improved exertional capacity.

The treatment of severe cardiac dysfunction and decompensated heartfailure may include inotropic drug therapies such as the catecholaminesdopamine and dobutamine or phosphodiesterase inhibitors milrinone oraminone. Although these agents may be beneficial in specific settings,they require administration of a drug, often by intravenous route, withsystemic side effects and the time-consuming involvement of skilledclinicians. Electrical stimulation therapies are attractive alternativesbecause they may be administered by implanted or external devices veryshortly after dysfunction appears or worsens and because their actionsmay be confined to the heart.

Delivering stimulation during the refractory period is a type ofnon-excitatory stimulation (NES) also denoted herein as refractoryperiod stimulation (RPS) causes release of catecholamines such asnorepinephrine within the tissue of the heart. This chemical release(modulated or regulated as described herein) results from selectiveelectrical stimulation of innervated portions of the myocardialsubstrate. Because the electrical stimulation is delivered during thenon-excitatory or refractory period wherein the discrete myocytes cannotcontract, only the interstitial nerve fibers effectively receivestimulation. This results in increased contractility of the cardiactissue which, in turn, results in increased pressure or flow, fewersymptoms of heart failure, and improved exertional capactity. NESneurostimulation employs one or more pulses applied shortly after asensed depolarization or an initial pacing pulse is delivered and aresulting ventricular contraction occurs. These NES pulses are deliveredduring the refractory period of the cardiac tissue such that they do notresult in another mechanical contraction or electrical depolarization.

Another type of electrical stimulation can be provided during thenonrefractory period of the cardiac cycle. This type of stimulationresults in an additional electrical depolarization and, whenappropriately timed, results in post extrasystolic potentiation (RPS).The additional depolarization, coming shortly after a firstdepolarization, is likely not associated with a sizable mechanicalcontraction. The contractility of subsequent cardiac cycles is increasedas described in detail in commonly assigned U.S. Pat. No. 5,213,098. Themechanism is understood to depend on calcium cycling within themyocytes. The early extrasystole tries to initiate calcium release fromthe sarcoplasmic reticulum (SR) too early and as a result does notrelease much calcium. However, the SR continues to take up furthercalcium with the result that the subsequent cardiac cycle causes a largerelease of calcium from the SR and the myocyte contracts morevigorously. Excitatory RPS stimulation requires an extra electricaldepolarization that is accompanied by a small mechanical contraction.

Another known treatment for HF patients involves using atrioventricular(AV) synchronous pacing systems, including DDD and DDDR pacing devices,cardiac resynchronization therapy (CRT) devices, and defibrillationsystems, to treat certain patient groups suffering heart failuresymptoms. These systems generally pace or sense in both the right atriumand right ventricle to synchronize contractions and contribute toventricular filling. Cardiac resynchronization devices extend dualchamber pacing to biventricular pacing to achieve better filling and amore coordinated contraction of the left and right ventricles. Thesepacing therapies result in greater pulse pressure, increased dP/dt, andimproved cardiac output. However, determining the appropriate pacingparameters is difficult. For example, optimizing the length of the AVdelay requires obtaining pressure data involving an extensive patientwork-up as set forth in commonly assigned U.S. Pat. No. 5,626,623. Thesepacing systems may also include atrial and ventricular defibrillators orother therapies for tachyarrhythmias. As a direct result of atachycardia or as a sequela, cardiac function may deteriorate to thepoint of greatly reduced cardiac output and elevated diastolic pressure.Rapid termination of tachycardias prevents worsening of heart failure.

The above-described therapies, including pacing, CRT, NES, anddefibrillation capability, may be used alone or in combination to treatcardiac dysfunction including HF. However, prior art systems have notachieved a comprehensive therapy regimen that coordinates thesemechanisms in a manner that is both safe and effective. Delivery ofelectrical stimulation as the heart tissue is becoming non-refractorycan trigger a tachyarrhythmia. This is particularly true if multiplehigh-amplitude pacing pulses are utilized. A second problem may be ashift in the magnitude of resulting potentiation or refractory intervaldue to the course of disease or medication. These may lead tounacceptable levels of potentiation performance, or loss of effectaltogether. Therefore, readily obtaining the appropriate timingparameters associated with this type of therapy is essential.

What is needed is a system and method that combines the known therapiesavailable for treating cardiac dysfunction including HF in a manner thatoptimizes mechanical function or cardiac output, while also minimizingany risks associated with possibly inducing an arrhythmia.

As discussed herein and in the related, incorporated-by-referenceapplications, an RSP therapy involves providing one or more pulses(e.g., one to a plurality of electrical pulses having programmablevalues, such as for instance 50 Hz pulse(s) with a pulse amplitude of4-10 volts, nominal pulse width of 1 to 3 ms) during the refractoryperiod of at least one ventricle. The pulses are delivered such that theventricles do not experience a second depolarization following deliveryof the pulse(s). The RPS therapy increases contractile function andstroke volume on subsequent contractions. The magnitude of the enhancedfunction is dependent on simulation timing, location, waveformcharacteristics, duration and frequency of RPS therapy delivery and thelike. The delivery location can include multi-site locations within oneor both ventricles (or via a coronary vein, a pericardial location,and/or single ventricular sites. The pulse or pulses can be bi-polar oruni-polar and the vectors of said pulse(s) can vary between anyavailable electrodes.

SUMMARY OF THE INVENTION

The current invention provides a system and method for deliveringtherapy for cardiac hemodynamic dysfunction, which without limitation,may include one of the following features:

Therapy for cardiac dysfunction that might otherwise require inotropicdrugs such as dobutamine, calcium, or milrinone;

Therapy for cardiac dysfunction that might otherwise require mechanicalaids such as intra-aortic balloon pumps, cardiac compression devices, orLV assist device pumps;

An implantable or external device that continuously monitors thepatient, automatically administering therapy when physiologic sensorsindicate need or the patient experiences symptoms;

Treatment for cardiac dysfunction as a result of drug overdose orhypothermia;

Combined with negative inotrope drug treatments such as beta blockers toimprove patient tolerance of these treatments;

Therapy for post ischemic cardiac dysfunction or stunning such asfollowing coronary vessel occlusion, thrombolytic drugs, angioplasty, orcardiac bypass surgery;

Support for the dysfunction that is associated with coming off cardiacbypass and the use of cardioplegia;

Therapy for rapid and poorly tolerated supra-ventricular tachycardias(SVT) by regularizing 2:1 AV block, lowering mechanical heart rate andimproving mechanical function, and may facilitate arrhythmiatermination;

Management of dysfunction following tachycardic events including AT, AF,SVT, VT, or VF including elective cardioversion and urgentdefibrillation and resuscitation;

Severe bouts of heart failure, worsening to cardiogenic shock,electromechanical dissociation (EMD) or pulseless electrical activity(PEA)

Acute deterioration of cardiac function associated with hypoxia ormetabolic disorders;

Intermittent therapy for HF such as prior or during exertion or forworsening symptoms;

Continuous therapy for HF to modify heart rate, improve filling andmechanical efficiency, and facilitate reverse remodeling and otherrecovery processes;

Scheduled therapy for HF including use for a specified interval of timeat a particular time of day or scheduled delivery every N cardiaccycles; and/or

Reducing AF burden as a result of reduced atrial loading and betterventricular function during therapy

Overview of a System Operating According to the Present Invention

A system constructed and operated according to the present inventionthat may be used to deliver the therapies discussed above may include asignal generator, timing circuit, and/or microprocessor control circuitof the type included in existing pacemaker or ICD systems as is known inthe art. Exemplary systems are shown in U.S. Pat. Nos. 5,158,078,5,318,593, 5,226,513, 5,314,448, 5,366,485, 5,713,924, 5,224,475 and5,835,975 each of which is incorporated herein by reference, althoughany other type of pacing and/or ICD system may be used for this purpose.In such systems, EGM sensing is performed by electrodes carried on leadsplaced within the chambers of the heart, and/or on the housing of thedevice. Alternatively, subcutaneous and/or external pad or patchelectrodes may be used to sense cardiac signals. Physiological sensorsmay likewise be carried on lead systems according to any of theconfigurations and/or sensing systems known in the art.

The following introductory material is intended to familiarize thereader with the general nature and some of the features of the presentinvention.

Brief Description of Electrodes and Leads for Use with the PresentInvention.

All embodiments of the present invention share a common need forelectrode configurations to deliver electrical stimulation energy wherenecessary and to time the delivery of this energy to achieve beneficialeffects while avoiding unsafe delivery (as further describedhereinbelow). For each therapy component described above, specificelectrode locations and geometries may be preferred. The locations forthe electrodes of this invention for stimulation include: use of largesurface area defibrillation coil electrodes in the heart or adjacent tothe heart; pacing electrodes at locations including RV apex, outflowtract, atrial locations, HIS bundle site, left side epicardium,pericardium or endocardium; sympathetic nerve regions near the cervicalor thoracic spine or nerves or adjacent vessels on or near the heart;transthoracic electrodes including paddles and patches, can electrode,temporary electrodes (e.g., epicardial, transvenous or post-operativeelectrodes), subcutaneous electrodes and multiple site stimulation.

In accordance with common biomedical engineering practices, stimulationtherapy is applied with minimized net charge delivery to reducecorrosion and counteract polarization energy losses. Both energyefficient therapy delivery and electrogram (EGM) sensing benefit fromlow polarization lead systems. Finally, the electrodes are preferablyconnected to fast recovery amplifiers that allow EGM sensing soon aftertherapy delivery.

Brief Description of Sensors for Use with the Present Invention.

The most fundamental sensors are those based on electrograms (ECG orEGMs) and reflect cardiac electrical activity. These sensors requireelectrodes located where they can readily detect depolarization andrepolarization signals as well as sense amplifiers for the monitoring ofheart rhythm and diagnosis of arrhythmias.

According to one embodiment, blood pressure sensors, accelerometers,flow probes, microphones, or sonometric crystals may be used to measureflow, force, velocity, movement of the walls of the heart, and/or toestimate the volume of the cardiac chambers. Parameters derived fromthese sensors can also be used to detect the onset and severity ofcardiac hemodynamic dysfunction. For example, HF decompensation may beindicated when a change in long-term diastolic cardiac pressure hasincreased while contractility of the heart derived from dP/dt rate ofrise of ventricular pressure has diminished.

Another embodiment of the invention may utilize changes in transthoracicor intracardiac impedance signals to sense cardiac motion andrespiratory movement. Changes in intra-thoracic impedance as a result ofpulmonary edema may also be used trigger RPS and/or NES stimulationtherapy.

In implantable or external devices, metabolic or chemical sensors suchas expired CO₂ and blood oxygen saturation, pH, PO₂, and/or lactate) maybe employed to reflect cardiac dysfunction.

Brief Description of Atrial Coordinated Pacing (“ACP”) According to theInvention.

According to one form of the invention, electrical stimulation to theupper and/or lower chambers of the heart may be delivered both duringrefractory and non-refractory periods to coordinate atrial contraction,stabilize the rhythm, and optimize cardiac output. This stimulation isimplemented via the present invention in a manner that minimizes thedangers associated with induced arrhythmias. Intrinsic atrial events arefollowed by ventricular events and manifest as sharp deflections ofatrial and ventricular electrograms (“AEGMs” and “VEGMs,” respectively).

According to one form of the invention, pacing occurs in the atrium at arate that is higher than the intrinsic rate. Even though 2:1 conductionis still present, the intrinsic ventricular depolarizations occur morefrequently because of the increased atrial rate. Yet another waveform“D” can be used to illustrate another form of ACP which the inventorsconsider a special case of ACP. In this case, an atrial coordinated paceis initiated a relatively short time period following a ventricular (oratrial) beat. Because of the AV block and the refractory state of theventricles, this Acp paced event does not conduct to the ventricle.Following this ACP paced beat an intrinsic depolarization is allowed tooccur in the atrium (As). This intrinsic beat conducts to the ventricle,resulting in a ventricular depolarization (Vs).

This aspect of the present invention allows a patient's natural AVconduction and intrinsic rate to emerge during the cardiac cycle,providing better rate control during RPS therapy. Extensions to providea lower rate limit by atrial and/or ventricular pacing are well known inthe art of pacing. ACP may be provided by an implantable device asillustrated here or be provided by transcutaneous pacing (TCP)stimulation timed from the surface ECG's R wave by stimuli of sufficientamplitude to capture both atria and ventricles.

Brief Description of NES/Sympathetic Neurostimulation per the Invention.

According to another aspect of the invention, non-excitatory electricalneural stimulation therapies are directed at sympathetic nerves in theneck, chest, mediastinum, and heart to enhance mechanical function bylocal release of catecholamines, such as norepinephrine. These therapiesare known as nonexcitatory electrical stimulation (NES) therapiesbecause they are not intended to cause cardiac tissue depolarization andcan be accomplished with electrode locations and stimulation timing thatavoid electrically exciting cardiac tissue. Electrodes near the heartdeliver one or more NES pulses within the refractory period of themyocardium. Of course, electrodes that direct electrical current awayfrom the myocardium may deliver electrical stimuli at various timesthroughout the cardiac cycle without directly exciting cardiac tissue.

Brief Description of Safety Lockout Rule(s) per the Present Invention.

Another aspect of the invention involves delivering electricalstimulation to the atrium and ventricles in a manner that optimizesresulting mechanical function including pressures and flows whileminimizing associated risks. Several features of the present inventionare provided to achieve this goal, including regulation of NES and RPStherapy delivery to attain the desired level of enhanced function, theuse of atrial coordinated pacing, or ACP, to improve rhythm regularityand hemodynamic benefit over NES and/or RPS alone, and a safety rule toinhibit or lockout RPS therapy when it is at risk of beingproarrhythmic, diminishing diastole and coronary blood flow, and/orreducing the beneficial effect on hemodynamics. Rapid heart rates areprime examples of when RPS therapy is counter productive and motivateuse of a safety lockout rule.

A safety lockout rule operates on a short term or beat-by-beat basis todisable RPS (and ACP, if enabled) if the V-V interval from the priorcycle is too short. Thus, ectopy will suppress RPS therapy as will sinustachycardia, other SVTs, VTs, and VF. The inventors have discovered thatthis rule is a key component of safe and effective RPS stimulationtherapy in a variety of situations.

Brief Description of Therapy Start and Stop Rules per the Invention.

The application of RPS and NES therapy according to the presentinvention may be altered by (i) a physician (based on laboratory resultsand the patient's signs and symptoms), (ii) by the patient (to help withanticipated or present symptoms such as associated with exertion), or(iii) automatically by device sensors that detect conditions responsiveto these stimulation therapies. In each of these cases there may bedistinct maximal therapy durations and termination criteria (or therapymay be ended by the physician or patient).

Automated sensor-governed initiation of stimulation therapies aredescribed herein. If there is no current arrhythmia, physiologic sensorsare employed to determine if cardiac hemodynamic dysfunction therapy isto be initiated. Blood pressure signals such as arterial, rightventricular, and/or left ventricular pressure sensors (which may beutilized to derive other discrete cardiovascular pressure measurements)may be used to obtain respective pressure measurements. Therapy may beinitiated when these measurements indicate a pressure change that dropsbelow or exceeds a predetermined threshold for an established period oftime. In one example depicted in detail herein, a severe level ofdysfunction (LV dP/dt max<400 mmHg/s) is observed during normal sinusrhythm for over six seconds. The pressure measurements may be weightedand/or combined to obtain a statistic used to trigger therapy delivery.The statistic may be used to develop long-term trend data used toindicate the onset and severity of HF and hemodynamic dysfunction.

In another aspect of the invention, RV pressure is used to derive RVend-diastolic and developed pressure, maximum pressure change as afunction of time (dP/dtmax), an estimate of pulmonary artery diastolicpressure (ePAD), an RV relaxation or contraction time constant (tau), orRV recirculation fraction (RF). These derived parameters are then usedto determine when the degree of dysfunction has exceeded an acceptablelevel such that therapy delivery is initiated. Parameters could bemeasured or computed as above and compared to thresholds, or sensorsignals could be processed and cardiac dysfunction identified throughtemplate matching and classification. Thresholds and/or classificationschemes may be periodically updated to reject any natural changes in thecondition of the patient as cause for therapy.

The present invention may also incorporate predicted hemodynamiccompromise through an extended analysis of cardiac cycle-length. Forexample, a long duration and rapid SVT, VT, or VF has a high likelihoodof producing dysfunction including acute HF decompensation, cardiogenicshock, or even electromechanical dissociation (EMD) or pulselesselectrical activity (PEA) after spontaneous termination orcardioversion. In such cases, a trial of stimulation therapy might beprogrammed without mechanical, metabolic, or chemical sensorconfirmation.

Other signals such as surface electrocardiogram (ECG) or electrogram(EGM) signals from electrodes within the patient's body may be used todetect dysfunction and heart failure (HF). For example, the ST segmentlevel of a cardiac cycle (PQRST) detected by an ECG may be monitored. Anelevated or depressed ST segment level has been found to be reliableindicator of ischemia, a condition known to be associated withdysfunction and HF. Alternatively, the duration of the Q-T interval mayalso be used to detect hemodynamic dysfunction. For example, a shortenedQ-T interval may indicate myocardial dysfunction. A template matchingalgorithm such as a wavelet classification algorithm may be used toidentify electrogram signals that are associated with hemodynamicdysfunction.

Chemical sensors may be used to initiate therapy, including sensors thatanalyze the blood to detect changes in lactate, O₂ saturation, PO₂, PCO₂and pH. Expired gas may be analyzed for PCO₂ as an indicator of cardiacoutput during resuscitation procedures. Pulse oximetry may providenoninvasive assessments of oxygen saturation and pulse plethysmogramsignals which have particular utility in the context of applying theinventive cardiac therapy with an automatic external defibrillator (AED)following cardioversion of a tachyarrhythmia. Therapy is then continueduntil the degree of dysfunction or HF reflected by these variables isless than a predetermined amount for a sufficient period of time.

Although pressure sensors figure prominently in the examples above (andin the '631 disclosure) a number of other sensors could reflectmechanical function. Intracardiac or transthoracic impedance changesreflect mechanical function, stroke volume, and cardiac output.Accelerometers or microphones within the body or applied externallysense serious cardiac dysfunction and monitor the response to therapy.Heart volume, dimension changes, and velocities may be measured byimplanted or external applications of ultrasound. Physiologic signalsmay continue to be sensed to determine if a therapy terminationcondition is met so that therapy may be terminated. In the context of anAED, for example, this may involve determining that a tachyarrhythmiahas terminated and that arterial pulse pressure has reached levelscompatible with recovery. The use, however, of a mechanical sensor suchas a pressure sensor or an accelerometer to determine whether or not toapply therapy has the drawback in that external treatments of PEA/EMDsuch as cardiac chest compressions may introduce error into thephysiologic signals, inhibiting or delaying therapy when it may beneeded. An additional aspect of the invention is to include not only amechanical sensor in or on the heart to detect cardiac function, but asecond sensor or a multitude of sensors away from the heart, such asinside the implantable device housing or can (acting as an indifferentelectrode). From this second sensor, CPR artifact (due to chestcompressions and the like) could be identified and subtracted to reveala more accurate assessment of true cardiac function.

Therapy is ordinarily automatically interrupted on detection of anarrhythmic event. Upon termination of the arrhythmic event, the therapymay be automatically reconfigured to reduce risk of re-induction.Therapy could also be interrupted on detection of a sufficient quantityof abnormal depolarizations such as a premature ventricular contraction(PVC). One or more PVCs could be detected through the use of rate limitsor through a template matching type algorithm such as a templatematching algorithm like a wavelet classification algorithm, or using aPR-logic® type rhythm discrimination scheme which is a proprietarydetection technique of Medtronic, Inc.

Brief Description of Identifying the Refractory Interval Per theInvention.

Although beneficial for cardiac function, the delivery of RPSstimulation pulses must be controlled so as to minimize the risk ofinducing an arrhythmia. This is best realized with reference to thetraces of an ECG or EGM signal aligned with a stimulus-intensity curveto show the intensity of pulses required to induce an extra systoleduring the time period following a ventricular depolarization whichcoincides to the QRS complex at an initial time zero (0). During theabsolute refractory period, the ventricles are refractory so thatanother depolarization will not be induced by delivery of electricalstimulation either directly or by applying electrical stimulation to anatrial chamber. Following this time, the tissue recovers so that anotherelectrical depolarization is possible upon the delivery of electricalstimulation to the cardiac tissue. The amount of electrical currentrequired to cause the extra systole during this time is represented bythe stimulus-intensity curve.

Initially the electrical current level required to capture the tissue ishigh but thereafter sharply decreases to a baseline level of roughly0.5-1 mA for an implanted pacing lead. For TCP via electrode pads orpaddles of an AED or external defibrillator the baseline level may be onthe order of 50-100 mA.

Also, the “vulnerable period” of the ventricles must be considered whenadministering RPS therapy. The vulnerable period represents a timeperiod during which an electrical pulse delivered at, or above, apre-determined amplitude has the risk of causing a VT or VF episode. Forexample, a pulse delivered at about 170 ms having an amplitude of 40 mAor more may induce an tachyarrhythmia.

The importance of identifying and techniques for identifying therefractory-nonrefractory boundary is described herein. Nonexcitatoryneurostimulation benefits arise from pulses anywhere in the refractoryperiod. NES neurostimulation delivered outside the refractory period isfrequently excitatory (and will be addressed in the excitatory RPSanalysis which follows herein below).

The level of enhancement or potentiation resulting from excitatory RPSstimulation therapy follows a potentiation response curve as furtherdescribed herein. The inventors have found that such electricalstimulation pulses delivered shortly after the refractory period endsproduce strong subsequent contractions. Further delays of thestimulation diminish the amount of potentiation. Stimulation too early(i.e., prematurely) results in no additional potentiation at all sincethe myocardium is refractory. As discussed with respect to thevulnerable period, the risk of arrhythmia induction is confined to arelatively narrow time interval just slightly longer than the refractoryperiod. However, the inventors have discovered that such a risk is quitelow if single RPS pulses are delivered according to the safety lockoutrule (briefly described above).

As a result, it is apparent that stimulation timing with respect to therefractory-nonrefractory period boundary is a critical aspect ofobtaining the desired response (NES or RPS) and controlling risks andbenefits of therapy delivery. The present invention provides for meansto determine this time from electrical, and/or mechanical sensor signalsand thereby enable safer and more effective stimulation therapies.

The inventors exploit the fact that the refractory period is closelyassociated with the Q-T interval, which may be derived from electrogramsignals or other physiologic sensor signals by techniques known in theart. The Q-T interval length is used to estimate the duration of therefractory period either directly, or by incorporating a function ofheart rate and sensing delays. In the case of RPS therapy, the Q-Tinterval length can be estimated by the time interval from an extrasystole stimulation pulse to an evoked T wave and would be slightlylonger than during a cardiac cycle not associated with PESP. This isbecause the extra depolarization caused by the RPS prolongs the QTinterval slightly.

Alternatively, an evoked response of the RPS stimulation could bemonitored to indicate whether the RPS therapy was delivered in therefractory period or not. For example, a number of electrical pulses areapplied to the myocardium, beginning during the refractory period. Theresult of each pulse is sensed on an EGM from either the stimulatingelectrode or an auxiliary electrode until an evoked response is sensed,indicating that the pulse caused an extra systole. At this point, nofurther pulses would be applied to minimize the risk of inducingarrhythmias.

In another example, a single pulse's amplitude and timing may bemanipulated until capture is detected by an evoked R wave. If capture islost, the stimulus pulse is delayed more, or amplitude increased, or thenumber of pulses in a RPS pulse train is increased. Also, thecharacteristics of a pressure waveform (or any other mechanical responsevariable) used to assess whether the RPS stimulation is/was capturingthe ventricles can be utilized when practicing the present invention.The presence of the extra systole could be identified by a smallventricular pressure pulse 5-80% of the size of the preceding pressurepulse or through a suitable algorithm such as a template matchingalgorithm.

The inventive system may also deliver optional non-excitatoryneurostimuli using a waveform including one or more pulses during therefractory period. To ensure that the NES stimulation does not enter thevulnerable period, the length of the refractory period is estimatedusing the mechanisms discussed above. If NES is exclusively intended,then detection of an extra systole—due to a capturing pulse deliveredoutside the refractory period—should result in a reduction of thestimulus delay time, amplitude, or pulse number.

As the refractory-nonrefractory boundary is very important and variesfrom patient to patient and even with a patient over time, with diseaseand drugs, these methods are to be employed periodically or continuallyto the stimulation timing algorithm portion of the device. If thisboundary information is not used to set pulse timing directly, it may beemployed to establish limits for the timing that is in turn set by aclinician or some automatic control algorithm such as that describednext.

Brief Description of Feedback Control of Stimulation Therapy Per theInvention.

According to yet another aspect of the invention, closed-loop feedbackfrom physiologic sensors is used to adjust the timing of the electricalstimulation so that therapy delivery may be tuned to further optimizecardiac function, maintain safety, and accommodate variations in theheart's responsiveness. The basic nonexcitatory neurostimulation (NES)response curve (a function of stimulus intensity in the refractoryperiod). Changes from patient to patient or within a patient (over time)may lead to different levels of enhanced function for a fixed NESstimulus. Conversely, maintenance of a desired level of enhancement mayrequire different stimulation times or intensities.

Sensor signal feedback may be used to govern stimulation timing in aclosed loop fashion to accommodate variations in responsiveness. Aphysician may react to physiologic information and adjust the electricalstimulation amplitude and timing. In the alternative, this reaction maybe accomplished by the device according to an algorithm referred to as acontroller. An elementary but useful and widely used family ofcontrollers is referred to as PID or P+I+D control. PID controllers workwith an error signal that reflects how far the sensor level is from atarget level or setpoint. The controller's output is a combination ofthe error signal, the integral of the error, and the derivative of theerror each scaled by a constant denoted P, I, and D, respectively.Practical controllers incorporate limits on their outputs andintegrators so as to keep the input to system they influence (called aplant) within reasonable bounds and maintain responsiveness.

An illustration of a functioning P+I controller based on RV dP/dtmax isdisclosed herein for use in conjunction with the present invention. Asan example, a setpoint of 700 mmHg/s was chosen for RPS stimulation froma baseline of 280 mmHg/s and the controller and therapy begun. The RPSstimulation pulse was automatically adjusted each cardiac cycle based onthe P+I controller within upper and lower limits. In the course of ourresearch we increased the controller's gains which led to oscillation.Using less gain it was possible to trade a little sluggishness inresponse for a great deal of robustness to variations in the plant'sresponse by exploiting feedback control.

It may be noted that stimulation time, as well as the maximum amplitude,pulse intervals, number of pulses in a train, change in the amplitude ofsequential pulses in the pulse train, and other parameters may beadjusted to achieve optimal cardiac performance for a given patient.This may be accomplished by monitoring sensed physiologic parameters ina closed-loop manner. The pulse train may then be adjusted accordinglyto maximize cardiac output or other indices of physiologic function. Forexample, rather than altering the timing of a single RPS pulse, thecontroller may alter the number and duration of a pulse train.

The NES stimulation may also be modulated to further improve cardiacfunction using physiologic signal monitoring in a closed-loopenvironment very similar to that discussed above for RPS therapy. Thevarious pulse trains found to be most effective for use in NES and RPStherapies are described in more detail in the related applicationsincorporated herein. The number of pulses, pulse amplitude, pulse shape,and any other aspect of the signal may be varied based on physiologicmeasurements to maximize cardiac output. Both the NES and RPS pulsetrains may be optimized to achieve maximum cardiac function. Both NESand RPS therapies need not be applied every cardiac cycle but could skipa specific number of cycles between applications (e.g., for one hour outof every six hours, manually triggered by a patient, triggered based ondetected physiologic state of a patient such as high or variable heartrate, etc.). The number of cycles skipped could also serve as a controlvariable.

Brief Description of Extensions to Tachyarrhythmia Management Devices.

An additional aspect of this invention is to change existing regimensfor the delivery of anti-tachycardia pacing (ATP) and shocks forcardioversion and defibrillation, given that cardiac stimulation therapymay be activated following these therapies. A flowchart illustratingthis aspect of the invention appears herein and is applicable for bothICDs (implantable cardiovertor defibrillators) and AEDs (automatedexternal defibrillators).

The first change to existing and prior art regimens is to increase thenumber of shocks beyond the present upper limit.

A second change is to increase the time between the later shocks in thesequence. With greater spacing, higher detection specificity would bepossible and minimize the potential risk of shock-induced myocardialdamage.

A third change would be to monitor the EGM for increased regularityand/or increased amplitude which may be an indicator as to when it wouldbe most efficacious to deliver the extra shocks.

An additional aspect of this invention is to modify existing rhythmrecognition algorithms of implanted and external therapy devices toaccommodate operating concurrently with therapy pulses delivered by apreexisting external or implanted device respectively. The sharp changesin electrogram slew rate associated with stimulation pulses may berecognized and ignored for the purpose of automated rhythm recognition.The devices analyze the effective heart rate and rhythm accordingly anddo not falsely detect or treat tachyarrhythmias.

Brief Description of a System Comprising the Present Invention.

A comprehensive flowchart depicting a high level view of the presentinvention showing the integration significant aspects for non-excitatoryRPS stimulation is included herewith. A representative heart andcardiovascular system is influenced by electrical therapies includingpacing, defibrillation, CRT, RPS and, optionally, NES stimulationtherapy. The heart and cardiovascular system may be monitored byelectrical, mechanical, and metabolic/chemical sensors. The signals fromthese sensors influence decisions to start or stop therapy, closed loopcontrol, refractory period detection, therapy safety lockout rules, andatrial coordinated pacing.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other advantages and features of the present invention will bemore readily understood from the following detailed description of thepreferred embodiments thereof, when considered in conjunction with thedrawings, in which like reference numerals indicate identical structuresthroughout the several views. The drawings are not drawn to scale and donot necessarily include all elements of every embodiment of the presentinvention.

FIG. 1 depicts the relationship of heart chamber EGM, pressure, flow,and volume during a cardiac cycle.

FIG. 2 is a schematic diagram depicting a multi-channel, atrial andbi-ventricular, monitoring/pacing IMD in which the present invention ispreferably implemented.

FIG. 3 is a simplified block diagram of one embodiment of IPG circuitryand associated leads employed in the system of FIG. 1 enabling selectivetherapy delivery and heart failure state monitoring in one or more heartchamber.

FIG. 4 is a simplified block diagram of a single monitoring and pacingchannel for deriving pressure, impedance and cardiac EGM signalsemployed in monitoring HF and optionally pacing the heart and deliveringRPS therapy in accordance with the present invention.

FIG. 5 depicts the delivery of therapeutic RPS stimulation,particularly, pacing energy pulse trains commenced during the refractoryperiod of the heart and continuing for a RPS delivery interval.

FIG. 6 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 7 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 8 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 9A through 9D are simple exemplary timing diagrams of variousembodiments of the therapy delivery according to the present invention.

FIG. 10 is a perspective view with portions exploded (and with someportions not depicted) of a heart and related sympathetic nerves whichmay be advantageously stimulated according to certain embodiments of thepresent invention.

FIG. 11 is a depiction of neurostimulation timing for electrodesdisposed near the cardiac tissue and relatively remotely from thecardiac tissue of a patient.

FIG. 12 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 13 is a set of three X-Y plots representing physiologic and therapyactivity according to the present invention.

FIG. 14 is a flow chart depicting an aspect of the present invention.

FIG. 15 is a flow chart depicting another aspect of the presentinvention.

FIG. 16 is a flow chart depicting yet another aspect of the presentinvention.

FIG. 17 is a flow chart depicting an additional aspect of the presentinvention.

FIG. 18 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 19 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 20 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 21 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 22 is a flow chart depicting an additional aspect of the presentinvention.

FIG. 23 is a set of four X-Y plots illustrating timing relationshipsbetween stimulation amplitude, mechanical function, arrhythmia risk and“net benefit” of therapy delivery according to the present invention.

FIG. 24 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 25 is a set of traces representing physiologic and therapy activityaccording to the present invention.

FIG. 26 is a flow chart depicting an additional aspect of the presentinvention.

FIG. 27 is a flow chart depicting an additional aspect of the presentinvention.

FIG. 28 is a flow chart depicting an additional aspect of the presentinvention.

FIG. 29 is a pair of X-Y plots showing the relationship betweenmechanical function (dP/dtmax) as a function of time and stimulationintensity, respectively.

FIG. 30 is a pair of X-Y plots showing the relationship betweenmechanical function (dP/dtmax) as a function of time and stimulationintensity, respectively.

FIG. 31 is a flow chart depicting an additional aspect of the presentinvention.

FIG. 32 is a flow chart depicting an additional aspect of the presentinvention.

FIG. 33 is a set of plotted empirical data representing physiologic andtherapy activity according to the present invention.

FIG. 34 is a flow chart depicting an additional aspect of the presentinvention.

FIG. 35 is a flow chart depicting an additional aspect of the presentinvention.

FIG. 36 is a set of traces representing physiologic and therapy activityaccording to the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following detailed description, references are made toillustrative embodiments for carrying out the invention. It isunderstood that other embodiments may be utilized without departing fromthe scope of the invention.

Before describing the preferred embodiments, reference is made to FIG. 1reproduced from the above-referenced '464 patent which depicts theelectrical depolarization waves attendant a normal sinus rhythm cardiaccycle in relation to the fluctuations in absolute blood pressure, aorticblood flow and ventricular volume in the left heart. The right atria andventricles exhibit roughly similar pressure, flow and volumefluctuations, in relation to the PQRST complex, as the left atria andventricles. It is understood that the monitoring and stimulation therapyaspects of this invention may reside and act on either or both sides ofthe heart. The cardiac cycle is completed in the interval betweensuccessive PQRST complexes and following relaxation of the atria andventricles as the right and left atria re-fill with venous blood andoxygenated blood. In sinus rhythm, the interval between depolarizationsmay be on the order of 500.0 ms to 1,000.0 ms for a corresponding sinusheart rate of 120 bpm to 60 bpm, respectively. In this time interval,the atria and ventricles are relaxed, and overall atrial size or volumemay vary as a function of pleural pressure and respiration. In the bloodpressure diagrams of FIG. 1, it may be observed that the atrial andventricular blood pressure changes track and lag the P-waves and R-wavesof the cardiac cycle. The time period T₀-T₁ encompasses the AV interval.

In patients suffering from cardiac insufficiency arising frombradycardia due to an incompetent SA node or AV-block, atrial and/orventricular conventional pacing may be prescribed to restore asufficient heart rate and AV synchrony. In FIG. 1 for example, atrialand/or ventricular pacing pulses would precede the P-wave and thedeflection of the QRS complex commonly referred to as the R-wave.Cardiac output may be reduced by the inability of the atrial orventricular myocardial cells to relax following atrial (T₀-T₁) andventricular (T₁-T₂) systolic periods. Prolonged systolic time periodsreduce passive filling time T₄-T₇ as shown in FIG. 1. Thus, the amountof blood expelled from the atria and/or ventricles in the next cardiaccycle may be less than optimum. This is particularly the case with HFpatients or other patients in whom the stiffness of the heart isincreased, cardiac filling during the passive filling phase (T₄-T₇) andduring atrial systole (T₀-T₁) is significantly limited.

It will be appreciated from the following description that themonitor/therapy delivery IMD of the present invention may be utilized toobtain the aforementioned parameters as stored patient data over aperiod of time and to deliver therapies for treating the heart failure.The physician is able to initiate uplink telemetry of the patient datain order to review it to make an assessment of the heart failure stateof the patient's heart. The physician can then determine whether aparticular therapy is appropriate, prescribe the therapy for a period oftime while again accumulating the stored patient data for a later reviewand assessment to determine whether the applied therapy is beneficial ornot, thereby enabling periodic changes in therapy, if appropriate. Suchtherapies include drug therapies and electrical stimulation therapies,including RPS and/or NES stimulation, and pacing therapies includingsingle chamber, dual chamber and multi-chamber (bi-atrial and/orbi-ventricular) pacing. Moreover, in patients prone to malignanttachyarrhythmias, the assessment of heart failure state can be takeninto account in setting parameters of detection or classification oftachyarrhythmias and the therapies that are delivered.

Accordingly, an embodiment of the invention is disclosed in detail inthe context of a multi-chamber pacing system that is modified to derivethe aforementioned parameters indicative of cardiac mechanicaldysfunction from sensors, sense electrodes and electrical stimulationelectrodes located in operative relation to one or more heart chamber.This embodiment of the invention may be programmed to operate as an AVsequential, bi-atrial and bi-ventricular, pacing system operating indemand, atrial tracking, and triggered pacing for restoring synchrony indepolarizations and contraction of left and right ventricles insynchronization with atrial sensed and paced events for treating HFand/or bradycardia. This embodiment of the invention is thereforeprogrammable to operate as a two, three or four channel pacing systemhaving an AV synchronous operating mode for restoring upper and lowerheart chamber synchronization and right and left atrial and/orventricular chamber depolarization synchrony. However, it will beunderstood that only certain of the components of the complexmulti-chamber pacing system described below can be selectivelyprogrammed to function or physically only incorporated into a simpler,single chamber, monitoring/stimulation system for deriving theparameters indicative of heart failure state.

In FIG. 2, heart 10 includes the upper heart chambers, the right atrium(RA) and left atrium (LA), and the lower heart chambers, the rightventricle (RV) and left ventricle (LV) and the coronary sinus (CS)extending from the opening in the right atrium laterally around theatria to form the great vein that extends further inferiority intobranches of the great vein. The cardiac cycle commences normally withthe generation of the depolarization impulse at the SA Node in the rightatrial wall. The impulse then conducts through the right atrium by wayof Internodal Tracts, and conducts to the left atrial septum by way ofBachmann's Bundle. The RA depolarization wave reaches theAtrio-ventricular (AV) node and the atrial septum within about 40 msecand reaches the furthest walls of the RA and LA within about 70 msec.Approximately 50 ms following electrical activation, the atria contract.The aggregate RA and LA depolarization wave appears as the P-wave of thePQRST complex when sensed across external ECG electrodes and displayed.The component of the atrial depolarization wave passing between a pairof unipolar or bipolar pace/sense electrodes, respectively, located onor adjacent the RA or LA is also referred to as a sensed P-wave.Although the location and spacing of the external ECG electrodes orimplanted unipolar atrial pace/sense electrodes has some influence, thenormal P-wave width does not exceed 80 msec in width as measured by ahigh impedance sense amplifier coupled with such electrodes. A normalnear field P-wave sensed between closely spaced bipolar pace/senseelectrodes and located in or adjacent the RA or the LA has a width of nomore than 60 msec as measured by a high impedance sense amplifier.

The depolarization impulse that reaches the AV Node conducts down thebundle of H is in the intraventricular septum after a delay of about 120msec. The depolarization wave reaches the apical region of the heartabout 20 msec later and is then travels superiorly though the PurkinjeFiber network over the remaining 40 msec. The aggregate RV and LVdepolarization wave and the subsequent T-wave accompanyingre-polarization of the depolarized myocardium are referred to as theQRST portion of the PQRST cardiac cycle complex when sensed acrossexternal ECG electrodes and displayed. When the amplitude of the QRSventricular depolarization wave passing between a bipolar or unipolarpace/sense electrode pair located on or adjacent to the RV or LV exceedsa threshold amplitude, it is detected as a sensed R-wave. Although thelocation and spacing of the external ECG electrodes or implantedunipolar ventricular pace/sense electrodes has some influence on R-wavesensing, the normal R-wave duration does not exceed 80 msec as measuredby a high impedance sense amplifier. A normal near field R-wave sensedbetween closely spaced bipolar pace/sense electrodes and located in oradjacent the RV or the LV has a width of no more than 60 msec asmeasured by a high impedance sense amplifier.

The normal electrical activation sequence becomes highly disrupted inpatients suffering from advanced HF and exhibiting Intra-atrialconduction delay (IACD), Left Bundle Branch Block (LBBB), Right BundleBranch Block (RBBB), and/or Intraventricular Conduction Delay (IVCD).These conduction defects give rise to great asynchrony between RVactivation and LV activation. Inter-ventricular asynchrony can rangefrom 80 to 200 msec or longer. In RBBB and LBBB patients, the QRScomplex is widened far beyond the normal range to between 120 msec and250 msec as measured on surface ECG. This increased width demonstratesthe lack of synchrony of the right and left ventricular depolarizationsand contractions.

FIG. 2 also depicts an implanted, multi-channel cardiac pacemaker, ICD,IPG or other IMD of the above noted types for restoring AV synchronouscontractions of the atrial and ventricular chambers and simultaneous orsequential pacing of the right and left ventricles. The pacemaker IPG 14is implanted subcutaneously in a patient's body between the skin and theribs. Three endocardial leads 16, 32 and 52 connect the IPG 14 with theRA, the RV and the LV, respectively. Each lead has at least oneelectrical conductor and pace/sense electrode, and a remote indifferentcan electrode 20 is formed as part of the outer surface of the housingof the IPG 14. As described further below, the pace/sense electrodes andthe remote indifferent can electrode 20 (IND_CAN electrode) can beselectively employed to provide a number of unipolar and bipolarpace/sense electrode combinations for pacing and sensing functions. Thedepicted positions in or about the right and left heart chambers arealso merely exemplary. Moreover other leads and pace/sense electrodesmay be used instead of the depicted leads and pace/sense electrodes thatare adapted to be placed at electrode sites on or in or relative to theRA, LA, RV and LV.

The depicted bipolar endocardial RA lead 16 is passed through a veininto the RA chamber of the heart 10, and the distal end of the RA lead16 is attached to the RA wall by an attachment mechanism 17. The bipolarendocardial RA lead 16 is formed with an in-line connector 13 fittinginto a bipolar bore of IPG connector block 12 that is coupled to a pairof electrically insulated conductors within lead body 15 and connectedwith distal tip RA pace/sense electrode 19 and proximal ring RApace/sense electrode 21. Delivery of atrial pace pulses and sensing ofatrial sense events is effected between the distal tip RA pace/senseelectrode 19 and proximal ring RA pace/sense electrode 21, wherein theproximal ring RA pace/sense electrode 21 functions as an indifferentelectrode (IND_RA). Alternatively, a unipolar endocardial RA lead couldbe substituted for the depicted bipolar endocardial RA lead 16 and beemployed with the IND_CAN electrode 20. Or, one of the distal tip RApace/sense electrode 19 and proximal ring RA pace/sense electrode 21 canbe employed with the IND_CAN electrode 20 for unipolar pacing and/orsensing.

Bipolar, endocardial RV lead 32 is passed through the vein and the RAchamber of the heart 10 and into the RV where its distal ring and tip RVpace/sense electrodes 38 and 40 are fixed in place in the apex by aconventional distal attachment mechanism 41. The RV lead 32 is formedwith an in-line connector 34 fitting into a bipolar bore of IPGconnector block 12 that is coupled to a pair of electrically insulatedconductors within lead body 36 and connected with distal tip RVpace/sense electrode 40 and proximal ring RV pace/sense electrode 38,wherein the proximal ring RV pace/sense electrode 38 functions as anindifferent electrode (IND_RV). Alternatively, a unipolar endocardial RVlead could be substituted for the depicted bipolar endocardial RV lead32 and be employed with the IND_CAN electrode 20. Or, one of the distaltip RV pace/sense electrode 40 and proximal ring RV pace/sense electrode38 can be employed with the IND_CAN electrode 20 for unipolar pacingand/or sensing.

In this illustrated embodiment, a unipolar, endocardial LV CS lead 52 ispassed through a vein and the RA chamber of the heart 10, into the CSand then inferiority in a branching vessel of the great vein 48 toextend the distal LV CS pace/sense electrode 50 alongside the LVchamber. The distal end of such LV CS leads is advanced through thesuperior vena cava, the right atrium, the ostium of the coronary sinus,the coronary sinus, and into a coronary vein descending from thecoronary sinus, such as the great vein. Typically, LV CS leads and LA CSleads do not employ any fixation mechanism and instead rely on the closeconfinement within these vessels to maintain the pace/sense electrode orelectrodes at a desired site. The LV CS lead 52 is formed with a smalldiameter single conductor lead body 56 coupled at the proximal endconnector 54 fitting into a bore of IPG connector block 12. A smalldiameter unipolar lead body 56 is selected in order to lodge the distalLV CS pace/sense electrode 50 deeply in a vein branching inferiorityfrom the great vein 48.

Preferably, the distal, LV CS active pace/sense electrode 50 is pairedwith the proximal ring RV indifferent pace/sense electrode 38 fordelivering LV pace pulses across the bulk of the left ventricle and theintraventricular septum. The distal LV CS active pace/sense electrode 50is also preferably paired with the distal tip RV active pace/senseelectrode 40 for sensing across the RV and LV as described furtherbelow.

Moreover, in a four-chamber embodiment, LV CS lead 52 could bear aproximal LA CS pace/sense electrode positioned along the lead body tolie in the larger diameter coronary sinus CS adjacent the LA. In thatcase, the lead body 56 would encase two electrically insulated leadconductors extending proximally from the more proximal LA CS pace/senseelectrode(s) and terminating in a bipolar connector 54. The LV CS leadbody would be smaller between the proximal LA CS electrode and thedistal LV CS active pace/sense electrode 50. In that case, pacing of theRA would be accomplished along the pacing vector between the activeproximal LA CS active electrode and the proximal ring RA indifferentpace/sense electrode 21.

Typically, in pacing/defibrillation systems of the type illustrated inFIG. 2, the electrodes designated above as “pace/sense” electrodes areused for both pacing and sensing functions. In accordance with oneaspect of the present invention, these “pace/sense” electrodes can beselected to be used exclusively as pace or sense electrodes or to beused in common as pace/sense electrodes in programmed combinations forsensing cardiac signals and delivering pace pulses along pacing andsensing vectors. Separate or shared indifferent pace and senseelectrodes can also be designated in pacing and sensing functions. Forconvenience, the following description separately designates pace andsense electrode pairs where a distinction is appropriate. With respectto the present invention, a subcutaneous electrode 45 coupled to medicalelectrical lead 43 may be added to or substituted for one or more of theleads or electrodes depicted in FIG. 2. If a subcutaneous electrode 45is utilized, a suitable defibrillation coil 47 may be coupled toappropriate high voltage circuitry to deliver a timed defibrillationpulse. While coil electrode 53 is depicted coupled to a portion of RVlead 32, such an electrode may be coupled to other portions of any ofthe leads depicted in FIG. 2, such as LV electrode 57. The coilelectrode 53, subcutaneous electrode 45 or other types of suitableelectrode configurations may be electrically coupled to low voltagepacing/sensing circuitry in addition to high voltage circuitry. As isknown, such electrodes may be disposed in a variety of locations in,around and on the heart.

Also depicted in FIG. 2 is an RV sensor 55 and an LV sensor 59 which maycomprise one or more of a variety of sensors as is known in the art.Preferably RV sensor 55 comprises an absolute pressure sensor, but otherpressure sensors may be utilized. In addition, RV sensor 55 may comprisean accelerometer, an impedance electrode, a saturated oxygen sensor, apH sensor, and the like. In addition, each of the leads could carry amechanical sensor for developing systolic and diastolic pressures and aseries of spaced apart impedance sensing leads for developing volumetricmeasurements of the expansion and contraction of the RA, LA, RV and LV.

Of course, such sensors must be rendered biocompatible and reliable forlong-term use. With respect to embodiments of the invention deliveringNES therapy, the preferred location for at least one electrode is in thecoronary venous system in close proximity to adjacent sympatheticnerves. In addition, one or more sensors may be disposed in or on thehousing 20 of IMD 14 such as sensor 11 depicted in FIG. 2.

FIG. 3A depicts a system architecture of an exemplary multi-chambermonitor/sensor 100 implanted into a patient's body 10 that providesdelivery of a therapy and/or physiologic input signal processing. Thetypical multi-chamber monitor/sensor 100 has a system architecture thatis constructed about a microcomputer-based control and timing system 102that varies in sophistication and complexity depending upon the type andfunctional features incorporated therein. The functions ofmicrocomputer-based multi-chamber monitor/sensor control and timingsystem 102 are controlled by firmware and programmed software algorithmsstored in RAM and ROM including PROM and EEPROM and are carried outusing a CPU, ALU, etc., of a typical microprocessor core architecture.Of course, such firmware and software may be modified in situ (e.g., invivo) and the operational characteristics may be adapted for aparticular situation or patient. A physician or clinician may change ormore parameter which will cause a change in the detection or response ofsuch algorithms. Oftentimes, discrete values may be changed such that adesired software routine is advantageously altered, although sometimesan entirely new set of operating software may be substituted for anexisting set of operating software, as is known in the art. Themicrocomputer-based multi-chamber monitor/sensor control and timingsystem 102 may also include a watchdog circuit, a DMA controller, ablock mover/reader, a CRC calculator, and other specific logic circuitrycoupled together by on-chip data bus, address bus, power, clock, andcontrol signal lines in paths or trees in a manner well known in theart. It will also be understood that control and timing of multi-chambermonitor/sensor 100 can be accomplished with dedicated circuit hardwareor state machine logic rather than a programmed micro-computer.

The multi-chamber monitor/sensor 100 also typically includes patientinterface circuitry 104 for receiving signals from sensors andpace/sense electrodes located at specific sites of the patient's heartchambers and/or delivering RPS stimulation to derive heart failureparameters or a pacing therapy to the heart chambers. The patientinterface circuitry 104 therefore comprises a RPS stimulation deliverysystem 106 optionally including pacing and other stimulation therapiesand a physiologic input signal processing circuit 108 for processing theblood pressure and volumetric signals output by sensors. For purposes ofillustration of the possible uses of the invention, a set of leadconnections are depicted for making electrical connections between thetherapy delivery system 106 and the input signal processing circuit 108and sets of pace/sense electrodes located in operative relation to theRA, LA, RV and LV.

As depicted in FIG. 3A, chemical/metabolic sensor input and/ormechanical sensor inputs are provided to the input signal processingcircuit 108. As described with respect to FIG. 2, a wide variety of suchsensors may be utilized when practicing the present invention.

A battery provides a source of electrical energy to power themulti-chamber monitor/sensor operating system including the circuitry ofmulti-chamber monitor/sensor 100 and to power any electromechanicaldevices, e.g., valves, pumps, etc. of a substance delivery multi-chambermonitor/sensor, or to provide electrical stimulation energy of an ICDshock generator, cardiac pacing pulse generator, or other electricalstimulation generator. The typical energy source is a high energydensity, low voltage battery 136 coupled with a power supply/POR circuit126 having power-on-reset (POR) capability. The power supply/POR circuit126 provides one or more low voltage power Vlo, the POR signal, one ormore VREF sources, current sources, an elective replacement indicator(ERI) signal, and, in the case of an ICD, high voltage power Vhi to thetherapy delivery system 106.

In order for the exemplary circuit of FIG. 3A to implement NES orcardiac defibrillation therapy according to the present invention, thetherapy delivery system 106 needs to utilize appropriate NES and highvoltage circuitry, respectively. If an NES therapy delivery electrode isdisposed remotely from the heart the delivery of NES therapy may occurindependent of the cardiac cycle (e.g., periodically approximatelybetween 10 ms and about ten seconds). While many different types ofpulses may be employed for NES therapy, one or more pulses of about 0.1to about 10 ms duration have been shown to provide the desired results.Effective NES therapy may be delivered using a variety of electrodeconfiguration (e.g., between one and several discrete electrodes). Also,standard tip, ring, coil, can, and subcutaneous electrodes may beutilized to effectively deliver NES therapy. While not specificallydepicted in the drawings, suitable external circuitry may be adapted forNES therapy delivery including use of surface electrode patches, pads orpaddles as well as pericardial electrodes. In particular, one or moreelectrodes disposed in the pericardial sac will be well positioned tostimulate the sympathetic nerves.

Virtually all current electronic multi-chamber monitor/sensor circuitryemploys clocked CMOS digital logic ICs that require a clock signal CLKprovided by a piezoelectric crystal 132 and system clock 122 coupledthereto as well as discrete components, e.g., inductors, capacitors,transformers, high voltage protection diodes, and the like that aremounted with the ICs to one or more substrate or printed circuit board.In FIG. 3A, each CLK signal generated by system clock 122 is routed toall applicable clocked logic via a clock tree. The system clock 122provides one or more fixed frequency CLK signal that is independent ofthe battery voltage over an operating battery voltage range for systemtiming and control functions and in formatting uplink telemetry signaltransmissions in the telemetry I/O circuit 124.

The RAM registers may be used for storing data compiled from sensedcardiac activity and/or relating to device operating history or sensedphysiologic parameters for uplink telemetry transmission on receipt of aretrieval or interrogation instruction via a downlink telemetrytransmission. The criteria for triggering data storage can also beprogrammed in via downlink telemetry transmitted instructions andparameter values The data storage is either triggered on a periodicbasis or by detection logic within the physiologic input signalprocessing circuit 108 upon satisfaction of certain programmed-in eventdetection criteria. In some cases, the multi-chamber monitor/sensor 100includes a magnetic field sensitive switch 130 that closes in responseto a magnetic field, and the closure causes a magnetic switch circuit toissue a switch closed (SC) signal to control and timing system 102 whichresponds in a magnet mode. For example, the patient may be provided witha magnet 116 that can be applied over the subcutaneously implantedmulti-chamber monitor/sensor 100 to close switch 130 and prompt thecontrol and timing system to deliver a therapy and/or store physiologicepisode data when the patient experiences certain symptoms. In eithercase, event related data, e.g., the date and time, may be stored alongwith the stored periodically collected or patient initiated physiologicdata for uplink telemetry in a later interrogation session.

In the multi-chamber monitor/sensor 100, uplink and downlink telemetrycapabilities are provided to enable communication with either a remotelylocated external medical device or a more proximal medical device on thepatient's body or another multi-chamber monitor/sensor in the patient'sbody as described above with respect to FIG. 2 and FIG. 3A (and FIG. 3Bdescribed below). The stored physiologic data of the types describedabove as well as real-time generated physiologic data andnon-physiologic data can be transmitted by uplink RF telemetry from themulti-chamber monitor/sensor 100 to the external programmer or otherremote medical device 26 in response to a downlink telemeteredinterrogation command. The real-time physiologic data typically includesreal time sampled signal levels, e.g., intracardiac electrocardiogramamplitude values, and sensor output signals. The non-physiologic patientdata includes currently programmed device operating modes and parametervalues, battery condition, device ID, patient ID, implantation dates,device programming history, real time event markers, and the like. Inthe context of implantable pacemakers and ids, such patient dataincludes programmed sense amplifier sensitivity, pacing or cardioversionpulse amplitude, energy, and pulse width, pacing or cardioversion leadimpedance, and accumulated statistics related to device performance,e.g., data related to detected arrhythmia episodes and appliedtherapies. The multi-chamber monitor/sensor thus develops a variety ofsuch real-time or stored, physiologic or non-physiologic, data, and suchdeveloped data is collectively referred to herein as “patient data.”

The physiologic input signal processing circuit 108 therefore includesat least one electrical signal amplifier circuit for amplifying,processing and in some cases detecting sense events from characteristicsof the electrical sense signal or sensor output signal. The physiologicinput signal processing circuit 108 in multi-chamber monitor/sensorsproviding dual chamber or multi-site or multi-chamber monitoring and/orpacing functions includes a plurality of cardiac signal sense channelsfor sensing and processing cardiac signals from sense electrodes locatedin relation to a heart chamber. Each such channel typically includes asense amplifier circuit for detecting specific cardiac events and an EGMamplifier circuit for providing an EGM signal to the control and timingsystem 102 for sampling, digitizing and storing or transmitting in anuplink transmission. Atrial and ventricular sense amplifiers includesignal processing stages for detecting the occurrence of a P-wave orR-wave, respectively and providing an ASENSE or VSENSE event signal tothe control and timing system 102. Timing and control system 102responds in accordance with its particular operating system to deliveror modify a pacing therapy, if appropriate, or to accumulate data foruplink telemetry transmission or to provide a Marker Channel® signal ina variety of ways known in the art.

In addition, the input signal processing circuit 108 includes at leastone physiologic sensor signal processing channel for sensing andprocessing a sensor derived signal from a physiologic sensor located inrelation to a heart chamber or elsewhere in the body.

Now turning to FIG. 3B, another system architecture for use inconjunction with the present invention is depicted. FIG. 3B is anexemplary system that may be utilized to deliver therapy byincorporating the system and method described above. Notably, thedepicted system includes a sense amplifier 534 to sense electricalsignals such as EGM signals using one or more leads placed within arespective chamber of the heart. These signals are used to determineatrial and ventricular depolarizations and Q-T length so that NES andRPS delivery is provided in a safe manner. One or more physiological orhemodynamic signals may be sensed using sensors such as those discussedabove. These additional signals, which are shown collectively providedon line 505, may be used to determine cardiac output so that therapy maybe initiated, terminated, and/or optimized.

The system of FIG. 3B further includes a timer/controller to control thedelivery of pacing pulses on output lines 500 and 502. This circuit,alone or in conjunction with microprocessor 524, controls intervallengths, pulse amplitudes, pulse lengths, and other waveform attributesassociated with the NES and RPS pulses. Output circuit 548 delivershigh-voltage stimulation such as defibrillation shocks under the controlof defibrillation control circuit 554.

Not all of the conventional interconnections of these voltages andsignals are shown in either FIG. 3A or FIG. 3B and many other variationson the illustrated electronic circuitry are possible, as is known tothose of skill in the art.

FIG. 4 schematically illustrates one pacing, sensing and parametermeasuring channel in relation to one heart chamber. A pair of pace/senseelectrodes 140,142, a sensor 160 (e.g., a pressure, saturated oxygen,flow, pH or the like), and a plurality, e.g., four, impedance measuringelectrodes 170,172,174,176 are located in operative relation to theheart chamber. The pair of pace/sense electrodes 140, 142 are located inoperative relation to the heart chamber and coupled through leadconductors 144 and 146, respectively, to the inputs of a sense amplifier148 located within the input signal processing circuit 108. The senseamplifier 148 is selectively enabled by the presence of a sense enablesignal that is provided by control and timing system 102. The senseamplifier 148 is enabled during prescribed times when pacing is eitherenabled or not enabled as described below in reference to themeasurement of the parameters of heart failure. The blanking signal isprovided by control and timing system 102 upon delivery of a pacing orRPS pulse or pulse train to disconnect the sense amplifier inputs fromthe lead conductors 144 and 146 for a short blanking period in a mannerwell known in the art. When sense amplifier 148 is enabled and is notblanked, it senses the electrical signals of the heart, referred to asthe EGM, in the heart chamber. The sense amplifier provides a senseevent signal signifying the contraction of the heart chamber commencinga heart cycle based upon characteristics of the EGM, typically theP-wave when the heart chamber is the RA or LA and the R-wave, when theheart chamber is the RV or LV, in a manner well known in the pacing art.The control and timing system responds to non-refractory sense events byrestarting an escape interval (EI) timer timing out the EI for the heartchamber, in a manner well known in the pacing art.

The pair of pace/sense electrodes 140, 142 are also coupled through leadconductors 144 and 146, respectively, to the output of a pulse generator150. The pulse generator 150, within RPS/pacing delivery system 106,selectively provides a pacing pulse to electrodes 140, 142 in responseto a RPS/PACE trigger signal generated at the time-out of the EI timerwithin control and timing system 102 in a manner well known in thepacing art. Or, the pulse generator 150 selectively provides a RPS pulseor pulse train to electrodes 140, 142 in response to a RPS/PACE triggersignal generated at the time-out of an ESI timer within control andtiming system 102 in the manner described in the above-referenced '098patent to cause the heart chamber to contract more forcefully, theincreased force depending upon the duration of the ESI.

The sensor 160 and/or other physiologic sensor is coupled to a sensorpower supply and signal processor 162 within the input signal processingcircuit 108 through a set of lead conductors 164 that convey power tothe sensor 160 and sampled blood pressure P signals from the sensor 160to the sensor power supply and signal processor 162. The sensor powersupply and signal processor 162 samples the blood pressure impingingupon a transducer surface of the sensor 160 located within the heartchamber when enabled by a sense enable signal from the control andtiming system 102. As an example, absolute pressure P, developedpressure DP and pressure rate of change dP/dt sample values can bedeveloped by sensor power supply and signal processor unit 162 or by thecontrol and timing system 102 for storage and processing as describedfurther below. The sensor 160 and a sensor power supply and signalprocessor 162 may take the form disclosed in commonly assigned U.S. Pat.No. 5,564,434.

The set of impedance electrodes 170, 172, 174 and 176 is coupled by aset of conductors 178 and is formed as a lead of the type described inthe above-referenced '717 patent that is coupled to the impedance powersupply and signal processor 180. Impedance-based measurements of cardiacparameters such as stroke volume are known in the art as described inthe above-referenced '417 patent which discloses an impedance leadhaving plural pairs of spaced surface electrodes located within theheart chamber. The spaced apart electrodes can also be disposed alongimpedance leads lodged in cardiac vessels, e.g., the coronary sinus andgreat vein or attached to the epicardium around the heart chamber. Theimpedance lead may be combined with the pace/sense and/or pressuresensor bearing lead.

A measure of heart chamber volume V is provided by the set of impedanceelectrodes 170, 172, 174 and 176 when the impedance power supply andsignal processor 180 is enabled by an impedance measure enable signalprovided by control and timing system 102. A fixed current carriersignal is applied between the pairs of impedance electrodes and thevoltage of the signal is modulated by the impedance through the bloodand heart muscle which varies as distance between the impedanceelectrodes varies. Thus, the calculation of the heart chamber volume Vsignals from impedance measurements between selected pairs of impedanceelectrodes 170, 172, 174 and 176 occurs during the contraction andrelaxation of the heart chamber that moves the spaced apart electrodepairs closer together and farther apart, respectively, due to the heartwall movement or the tidal flow of blood out of and then into the heartchamber. Raw signals are demodulated, digitized, and processed to obtainan extrapolated impedance value. When this value is divided into theproduct of blood resistivity times the square of the distance betweenthe pairs of spaced electrodes, the result is a measure of instantaneousheart chamber volume V within the heart chamber.

In accordance with the present invention, the IMD measures a group ofparameters indicative of the state of heart failure employing EGMsignals, measures of absolute blood pressure P and/or dP/dt, saturatedoxygen, flow, pH or the like and measures of heart chamber volume V overone or more cardiac cycles.

The steps of deriving the RF, MR, EES, and tau parameters indicative ofthe state of heart failure are more fully described in the '631disclosure and will not be repeated here. For the uninitiated thefollowing description is provided; however, if additional details aredesired the reader is directed to the '631 disclosure. These parametersare determined periodically throughout each day regardless of patientposture and activity. However, the patient may be advised by thephysician to undertake certain activities or movements at precise timesof day or to simultaneously initiate the determination of the parametersthough use of a magnet or a remote system programmer unit (not depicted)that is detected by the IMD. Certain of the parameters are only measuredor certain of the parameter data are only stored when the patient heartrate is within a normal sinus range between programmed lower and upperheart rates and the heart rhythm is relatively stable. The parameterdata and related data, e.g., heart rate and patient activity level, aredate and time stamped and stored in IMD memory for retrieval employingconventional telemetry systems. Incremental changes in the stored dataover time provide a measure of the degree of change in the heart failurecondition of the heart. Such parameter data and related data may beread, reviewed, analyzed and the like and the parameter data may bechanged based on a current patient condition, a patient history, patientor physician preference(s) and the like.

Turning to FIG. 5, the timing diagram illustrates the timing of deliveryof stimulation to a heart chamber in relation to a timed interval from asensed or paced event as well as alternative pulse waveforms of theRPS/NES stimulation. In accordance with one aspect of the presentinvention, a therapeutic stimulation delay illustrated in tracing (e) istimed out from a sensed or paced event (e.g., the illustrated V-EVENTs)that for NES is shorter than the refractory period of the heartpersisting from the sensed or paced event. A stimulus pulse train isdelivered to the atria and/or ventricles in the depicted therapydelivery interval of tracing (f) commencing after time-out of the delayso that for NES therapy delivery at least the initial pulse(s) of thepulse train fall within the end portion of the refractory period. Thepulses for RPS therapy delivery is intended to be supra-threshold innature, that is, of sufficient energy to depolarize the heart when theyare delivered in the non-refractory period of the heart cycle so thatthe heart is captured by at least one of the RPS pulses falling outsidethe refractory period. The initial pulses delivered during therefractory period can also potentiate the heart. For simplicity ofillustration, the tracings (f)-(j) are expanded in length, and thedepolarization of the heart that they cause is not depicted in tracing(a). The amplitude and number of refractory interval pulses and RPSpulses in each therapy pulse train and the spacing between the pulsesmay also differ from the illustrated tracings (g)-(j).

The ventricular sense or pace event detected in tracing (b) alsotriggers the timing out of an escape interval in tracing (c) which maybe terminated by the sensing of a subsequent atrial or ventricularevent, depending on the operating mode of the system. The first depictedsequence in FIG. 5 shows the full time-out of the escape interval intracing (c), the refractory period in tracing (d), and the therapy delayand delivery intervals in tracings (e) and (f). The therapy delay andtherapy delivery intervals can be derived as a function of an intrinsicV-V or V-A escape interval derived by measuring and averaging intervalsbetween intrinsic ventricular and/or atrial sense events or pacedevents. The therapy delay can also be determined from a measurement ofthe Q-T interval. As illustrated, the therapy delay in tracing (e)delays delivery of the therapy pulse train until the QRS complex ends orabout 40-60 ms after the V-EVENT well before the start of the vulnerableperiod of the heart which occurs near the end of the T-wave. The therapydelivery interval is timed to time-out well before the end of thepreviously derived V-V or V-A escape interval, but is extended for easeof illustration of the pulse trains in tracings (f)-(j).

The therapy stimulation energy is delivered in the form of a burst of Xconstant or variable energy stimulation pulses separated by a pulseseparation interval between each pulse of the burst. All of the pulsescan have the same amplitude and energy as shown in waveform 3 of tracing(i). Or the leading and/or trailing pulses of the pulse train can haveramped amplitudes similar to the waveforms 1 and 2 illustrated intracings (g) and (h). In tracings (g) and (h), the ramp up leading edgeamplitudes of a sub-set of the pulses of the burst are shown increasingfrom an initial amplitude to a maximum amplitude. In tracing (g), theramp down trailing edge amplitudes of a further sub-set of the pulses ofthe burst are shown decreasing from the maximum amplitude to aterminating amplitude.

Alternatively, the initial set of pulses delivered during the refractoryperiod can have a higher pulse amplitude or width as shown by waveform 4illustrated in tracing (j). The high energy pulses delivered during therefractory period can enhance potentiation during subsequent heartcycles. Tracing (j) also illustrates alternative numbers and spacing ofthe pulses of the pulse train, and it will be understood that thisembodiment can also employ the number of pulses and pulse spacing ofwaveforms 1-3.

In addition, it may be desirable to avoid delivering any therapy pulsesin the vulnerable period of the heart near the end of the T-wave,particularly if high energy pulses are delivered during the refractoryperiod. Tracing (j) also illustrates a vulnerable period delay betweenthe high energy pulses delivered during the refractory period and thelower energy RPS pulses to avoid delivering any pulses during thevulnerable period of the heart. It would also be possible to lower thepulse energy of the pulses delivered later in the refractory period.

The therapy delivery capability is preferably implemented into a systemthat may include conventional pacing therapies and operating modes aswell as cardioversion/defibrillation capabilities or as a stand alonesystem for simply providing pulse therapies to effect potentiation ofmyocardial cells between sensed PQRST complexes shown in FIG. 5.

Detailed Description of Atrial Coordinated Pacing Per the Invention.

FIG. 6 illustrates untreated chronic HF dysfunction with a rapid sinusrhythm (100 bpm) in an ambulatory model of chronic HF. In FIG. 6,regular atrial and ventricular electrograms (AEGM and VEGM) areillustrated, and a measurement of an index of contractile function (LVdP/dtmax) is shown which is derived from LV pressure (LVP). In FIG. 6the valued of LV dP/dtmax is shown to be about 900 mmHg/s.

FIG. 7 illustrates HF dysfunction treated with RPS therapy and atrialcoordinated pacing (ACP) according to the present invention. In FIG. 7,the subject with chronic HF is continuously treated with ventricular RPStherapy (channel marked Vtherapy) and atrial coordinated pacing ACP(channel marked ACP). The result is a stable rhythm at a lower rate(around 50 bpm) with sustained contractile enhancement (LV dP/dtmax isimproved to about 1800 mmHg/s). It can be seen that occasionally, whenthe intrinsic atrial rate drops, an atrial pace event occurs to initiatea cardiac cycle (see Apace event aligned with the vertical line labeled“MI rate support” (at the right of FIG. 7). One result of RPS therapyand ACP therapy is a slower rhythm with enhanced mechanical functionoccurring on the portion of the cardiac cycle with intrinsic AVconduction and natural ventricular depolarization. This therapy regimencauses a forced deceleration of the cardiac rhythm. This type ofstimulation therapy also appears suitable for HF patients having intactAV conduction that suffer from SVT (supraventricular tachyarrhythmia) aswill be further described and illustrated with respect to FIG. 36(below).

Referring now to FIG. 8, rhythm irregularities are depicted during RPStherapy (without ACP). In the left portion of FIG. 8, HF dysfunction istreated with RPS therapy and a form of ACP consisting of MI pacing at120 bpm with 2:1 AV block. In the right portion of FIG. 8, HFdysfunction is treated with RPS therapy without AAI pacing. Although itcan be appreciated that contractility remains improved (about 1900mmHg/s), variations in refractoriness and intrinsic intervals commonlyresult in intermittent 1:1 and 2:1 AV conduction (seen at right of FIG.8). The heart tissue is not guaranteed sufficient time in diastole forgood filling, coronary flow, and ion flux stabilization. As a result,the peripheral pulse rate is variable, mechanical enhancement is lessconsistent, and the heart more prone to arrhythmias and metabolicintolerance.

FIG. 9A-9D is a schematic of atrial coordinated pacing (ACP) from theperspective of an implantable medical device, such as an ICD orpacemaker. In FIG. 9A, a normal sinus rhythm is depicted in which eachatrial instrinsic depolarization (denoted As for atrial sense event)conducts to the ventricles and produces an intrinsicly conductedventricular depolarization (labeled Vs for ventricular sense event). Ifthe intrinsic atrial rate is too low, atrial pacing (denoted Ap) maysubstitute for atrial sense events shown. With respect to FIG. 9B,introduction of ventricular stimulation therapy pulses (either RPS aloneor combined RPS and NES− denoted Vth) occurs and the ventricles becomerefractory a second time. As a result, a 2:1 conduction pattern mayarise in which every other atrial sense event is blocked. This patternis often unstable (see FIG. 8 above) and may result in effectiveventricular rates that are too slow (brady) or too fast (tachy).

With respect to FIG. 9C, which depicts a simple form of ACP, the atriaare paced at a rate faster than the intrinsic rate and the 2:1 block isregularized. This approach helps when the result of the case depicted inFIG. 9B was an effective ventricular rate that was too slow or tooirregular, but does not allow the subject's physiology to set heartrate, paces the atrium frequently, and may result in an excessive heartrate.

With respect to FIG. 9D, which depicts a preferred implementation ofACP, the atria are paced for the purpose of coordination (denoted “Acp”)after the ventricular sense event and around the same time as the Vthpulse or pulses. The ACP pace events do not conduct to the ventriclesbut reset the sinus node. Thus, the next atrial sense event occurs at atime governed by physiologic demand. The resulting “potentiated” beatsare thus advantageously preceeded by adequate filling time, bettercoronary flow, and more time for myocye ion fluxes to normalize.

Of course, as is well known in the art, atrial pacing may be employed ifthe intrinsic atrial rate drops too low (see FIG. 7—above) and maintainthe advantages discussed. Furthermore, if AV or ventricular conductionis impaired, ventricular pacing at an appropriate AV interval may alsobe employed. This may take the form of single or multiple site (e.g.biventricular) pacing.

For TCP or transthoracic pacing such as employed with an AED, althoughatrial sensing is not readily available (nor is atrial pacing) ACP asillustrated by FIG. 9D can still be performed. To practice such ACP, aTCP therapy pulse triggered from a sensed R-wave (or pacing pulse) wouldinduce depolarization in both atria and ventricles simultaneously andachieve RPS and ACP according to the present invention.

As is known in the art, timing and delivery of ACP pulses are preferablyunder microprocessor control, such as depicted in the system diagrams ofFIG. 3A and FIG. 3B. Also, such timing parameters are programmable andmay be adjusted or modified by a clinician.

With general reference to FIG. 6 through FIG. 9, it should beappreciated that ventricular therapy, denoted Vth, includes RPS andoptionally nonexcitatory neurostimulation (NES). The determinants oftiming and amplitude of the Vth pulse or pulses have been discussedpreviously in the '631 disclosure and elsewhere in this inventiondisclosure. Intervals from the preceding Vs or Vp event are chosen toyield the desired effects (excitatory or nonexcitatory) and amplitude ofpotentiation (RPS). Furthermore, the choice of ACP timing to implementsafe and physiologic enhancement of cardiac function is also important.If the Vth therapy pulse is vetoed by safety rules or other reasons ordoes not capture, the ACP pulse is withheld. When excitatory ventriculartherapy is discontinued, so too is ACP. If this is not done, thereresults a form of pacemaker mediated tachycardia (PMT). Unlesspotentiation is intended to come from conduction of the ACP pulse'sdepolarization, the goal of ACP is to guarantee atrial depolarizationand AV block. These considerations result in bounds for ACP timing thatwill be discussed for the case of therapy delivered every cardiac cycle.

For example, let X represent the time from the potentiated Vs (or Vp) tothe scheduled delivery of ACP. Let Y similarly represent the time fromthe potentiated Vs (or Vp) to the scheduled delivery of Vth. These rulesbehind calculation of the value of Y are described in the '631disclosure, and in the present patent disclosure with respect todiscussion and illustrations regarding feedback control, the safetylockout rules, and the identification and determination of refractoryinterval. The value of X must be larger (i.e., longer) than the A-Arefractory period (which is often approximately 200-300 ms). The valueof X must also be chosen such that the resulting depolarization passesthe AV node or ventricle while in a refractory state. Let RV denote theV-V refractory period and RA denote the A-A refractory period. Furtherlet AV denote the AV conduction delay (that is the time from an Apace toa Vsense event, less any delays associated with sensing itself). Then Xmust satisfy the following pair of inequalities:X>R_(A) and Y−AV≦x≦Y−AV+R _(V)

Experience has shown values of X in the range of 150 to 200 ms tosatisfy both inequalities and yield the desired effects. This generallyplaces ACP shortly before excitatory Vth pulses. The reader should notethat ACP is subject to the same safety veto rules as Vth (discussed inrelation to safety lockout rules section of this patent disclosure) butfaces an additional challenge. That is, if the Vth pulse amplitude(s) issub-threshold or entirely within the refractory period, no potentiationresults. Although the arrhythmia risk is essentially zero, the subjectis deprived of the benefit of RPS therapy. However, if ACP is deliveredabove threshold in this setting, this could raise the ventricular rateby conducting to the ventricles. The resulting Vsense initiates anotherACP and establishes a PMT with cycle length of X+AV. The presentinvention therefore incorporates an additional ACP lockout rule thatends this type of PMT after a single beat. This lockout rule requiresthat if there is no atrial event (sense or pace) over the previouscardiac cycle (from Vsense to Vsense) or in a sufficient interval, thenthe ACP is selectively vetoed for the next N cardiac cycles and evidencesought of extrasystole capture.

Detailed Description of Non-Excitatory Neurostimulation.

Now turning to FIG. 10 in which sympathetic innervation of the heart andelectrode locations for nonexcitatory stimulation (NES) is depicted in apartially exploded perspective view with portions removed for ease ofinspection. Significant elements in FIG. 10 are identified as thefollowing: spinal cord, cervical and thoracic segmental nerves(collectively denoted by the letter “A”), cervical and thoracic chainganglia (up and down near the vertebral bodies at back of thorax(denoted with the letter “B”), autonomic nerves traveling through thethorax and mediastinum toward great vessels and the heart 10 andincluding the ansa subclavia (denoted with the letter “C”), variouscardiac nerves often traveling near coronary vessels (denoted with theletter “D”), and cardiac nerves in the myocardium (denoted with theletter “E”). Electrodes (such as depicted in FIG. 2) may be positionedanywhere along these pathways to direct electrical stimulation currentto these sympathetic nerves and avoid painful stimulation of othernerves or organs and avoid pacing the heart 10. Alternatively,subcutaneous electrodes such as the can electrode or other subcutaneouspatch electrodes may be employed to stimulate broadly regions A-E andreserved for severe dysfunction including cardiogenic shock andelectromechanical dissociation (EMD) or pulseless electrical activity(PEA). Furthermore, subcutaneous patch, pad electrodes or paddleelectrodes may be similarly employed to direct electrical current torelated sympathetic neural tissue in accordance with this aspect of thepresent invention.

Now turning to FIG. 11 which depicts neurostimulation and the cardiacrefractory period, it can be seen that a stimulation threshold curve ofcardiac muscle and the electrode location for nonexcitatoryneurostimulation govern stimulation pulse timing. Adjacent to the heartwhere stimulation could cause capture, the NES pulses are deliveredduring the refractory period and/or remain subthreshold (i.e., below athreshold magnitude). Further from the cardiac tissue, the stimulationpulses may have different amplitude and may be more widely spaced.

FIG. 12 is a diagram illustrating an example of NES therapy delivery.This diagram illustrates the effects of stimulating sympathetic nervesnear the heart with increasing amounts of current (1, 2.5, and 5 mA,respectively). Such NES stimulation during the refractory period resultsin a dose dependent increase of aortic blood pressure (AoP),contractility (LV dP/dt), heart rate, and cardiac output. The magnitudeof the response may be similarly controlled by adjusting the durationand/or number of pulses in the NES pulse train. The NES therapy timingand stimulus parameters are preferably controlled by a microprocessor orhardware and programmable with input values determined by algorithms orclinicians, such as depicted in the system diagrams of FIG. 3A and FIG.3B.

Detailed Description of Safety Lockout Rules.

FIG. 13A through 13C illustrate the consequences of RPS stimulationduring a tachycardia event. The inventors have discovered that it ispreferable, if not absolutely necessary, to cease delivery of excitatoryRPS stimulation therapy during tachycardias. In the condition depictedin FIG. 13A, the ventricular mechanical rate is low (60 bpm), theamplitude of the potentiation is large, and there is sufficient time indiastole for ventricular filling. In the condition depicted in FIG. 13Bthe heart rate has effectively doubled (i.e., increased to 120 bpm), andwhile the amplitude of potentiation remains large the diastolic time isshorter. In the condition depicted in FIG. 13C, the heart rate is evenhigher (i.e., at about 150 bpm) and the extrasystole encroaches severelyon the cardiac cycle's time in diastole. Furthermore, at these highheart rates RPS potentiation diminishes. The RPS stimulation transformsthe 150 bpm tachycardia to a ventricular tachycardia with mechanicalalternans and an effective rate of 300 bpm. Heart rates this high arepoorly tolerated and will further contribute to cardiac dysfunction,heart failure decompensation, and predispose a person subjected to suchan effective heart rate to VT or VF.

Referring now to FIG. 14, a flow chart for a safety lockout rule forapplication of excitatory RPS stimulation is depicted. It can beappreciated that each new cardiac cycle begins with a ventricular event(Vevent) that is either a Vpace or Vsense. The safety lockout rule hasveto power over the decision to deliver excitatory RPS stimulation tothe ventricle and possibly atrial coordinated pacing (ACP) during thiscycle. If the prior V-V interval is greater than a threshold value, RPSand/or ACP pulses are enabled for this cycle. Should the V-V interval betoo short, stimulation therapy is aborted. This prevents stimulationtherapy from further adding to the arrhythmic potential of an intrinsicpremature ventricular contraction (PVC). Stimulation with a shortcoupling interval, particularly if immediately following other shortintervals is significantly pro-arrhythmic and is, of course, to beavoided. The safety lockout rule also prevents application of excitatorytherapy during various tachycardias including sinus tachycardia,supraventricular tachycardia (SVT), ventricular tachycardia (VT), orventricular fibrillation (VF). The threshold used may either be a fixedvalue or derived from other hemodynamic or electrogram based parametersand is typically 400-600 ms. The safety lockout rules may operate usinga variety of timing schemes which are microprocessor or hardwarecontrolled and programmable with input values determined by algorithmsor clinicians, such as depicted in the system diagrams of FIG. 3A andFIG. 3B.

Detailed Description of Start-Stop Rules.

Referring now to FIG. 15, which is a top level flow chart governinginitiation and termination of stimulation therapies according to thepresent invention. If therapy is not currently enabled, therapy can beinitiated by a clinician, the patient, or the device. The clinician isable to preempt an assessment by the device or patient to beginstimulation therapy based on consultation with the patient, signs orsymptoms of cardiac dysfunction, or lab results. If begun in this mannerthe therapy may have a duration and termination criteria different frompatient or device initiated therapy. Similarly, the patient, as a resultof symptoms or anticipated exertion may preempt the device and begintherapy. Finally, the device may automatically begin therapy based onpreprogrammed time of day or due to sensor signals, includingelectograms, hemodynamic, activity sensor signals, and other physiologicsensor signals. Therapy may be discontinued by clinician command,patient request, or device based criteria that include sufficienttherapy duration and sensor assessment of sufficient benefits or risks.

In FIG. 16, which is a more detailed flow chart of automatedsensor-governed initiation of stimulation therapies. Based onelectrogram (EGM) sensor signals derived from a patient (both presentlyand recently), the device first looks for and treats cardiac rhythmproblems before moving on to examine other sensor signal data. If thecardiac rhythm appears satisfactory, then hemodynamic sensors such aspressure and flow are employed. If there is sufficient dysfunction andduration, therapy begins. Metabolic or other physiologic sensor severityand duration assessments as well as a prescheduled time of day criteriamay also initiate stimulation therapies according to the presentinvention.

With respect to FIG. 17, which is an expanded diagram of suspension ortermination of stimulation therapies according to the present invention.If a tachyarrhythmia develops of sufficient rate or duration (e.g.,which exceeds a predetermined rate or duration threshold), the therapyis either temporarily suspended or halted altogether and the arrhythmiatreated by any of a variety of well-known means such as antitachycardiapacing (ATP), cardioversion, or the like. Upon restoration of a morenormal rhythm, the device may or may not re-enable automatic therapydelivery. The device may also readjust its stimulation therapyparameters such as timing and amplitude to achieve a lower arrhythmiarisk profile, trading physiologic benefit for arrhythmia risk (on thepresumption that the stimulation therapies either caused or predisposedthe subject to this arrhythmia). If the rhythm remains satisfactory, thedevice checks if either duration or combined hemodynamic improvement andduration criteria are met. If so, the therapies are again eithertemporarily suspended or halted altogether. Automated therapies may bere-enabled after a period of time or left disabled. In order to preventmultiple brief cyclic applications of therapy, the improvement criteriamay be different from the initiation criteria to implement ahysteresis-like effect. Therapies may also be disabled upon reaching afixed number of therapy applications and require an external override torestart.

Referring now to FIG. 18, which depicts termination of a tachyarrhythmiaand initiation of therapy for cardiac dysfunction, FIG. 18 illustratessome the therapy initiation rules described above. As can be seen withreference to FIG. 18, a tachyarrhythmia is ended at about 17:46:05 andelectrogram sensors (here the surface electrocardiogram (ECG) confirmthe existence of a reasonable rhythm and rate. However, hemodynamicsensors such as arterial blood pressure (ABP) and left ventricularpressure (LVP) confirm a severe level of dysfunction (e.g. LVdP/dtmax<400 mmHg/s) that is sustained for over 6 seconds and over 12cardiac cycles. As a result, the decision to initiate stimulationtherapies occurs at about 17:46:15. A prompt response of arterial bloodpressure, LVP, coronary blood flow, aortic blood flow, and LV dP/dtmaxis seen coincident with the application of RPS therapy pulses(Vtherapy).

In FIG. 19, an initiation of and response to RPS stimulation therapy isdepicted. In other conditions such as HF, not necessarily associatedwith a preceding or concurrent tachyarrhythmia, cardiac dysfunction maydeteriorate to the point where device initiated therapy is required. Theonset of such cardiac dysfunction may either be gradual or sudden butupon establishing sufficient severity and duration, RPS stimulationtherapy is begun. The excitatory RPS therapy shown here provides muchneeded increases of arterial blood pressure (ABP), coronary flow(CorFlow) and aortic flow (AorFlow) and the LV dp/dtmax value more thandoubles from pre-RPS therapy in approximately five seconds.

FIG. 20 depicts termination of RPS therapy based on duration andresponse criteria. In FIG. 20, the termination criteria is met and RPSstimulation therapy is halted. In this case, stimulation therapyconsists of atrial-only RPS stimulation therapy pulses (Ath) whichcapture and reset the sinus node, are conducted to the ventricles, andproduce atrial and ventricular RPS due to natural conduction. In thissequence, the patient has maintained a good RV pressure (RVP) and LVdP/dtmax for over 30-60 seconds, and therefore the atrial-only RPSstimulation therapy is halted. Although the heart rate accelerates andcontractility diminishes, cardiac function has recovered verysignificantly from the levels shown in FIG. 18 and FIG. 19 ((justdescribed).

Now turning to FIG. 21 which depiction a dramatic example of lifesavingRPS stimulation therapy. FIG. 21 illustrates (and clearly demonstrates)that post extra-systolic potentiation stimulation therapy can facilitaterapid recovery of cardiac function following a long duration of pacedtachyarrhythmia in an anesthetized canine subject.

In FIG. 21, the trace denoted “ECG” is a surface ECG record, the tracedenoted “ABP” is a record of arterial blood pressure measured via acatheter in the aorta of the subject, the trace denoted “RVP” is arecord of blood pressure measured within the right ventricle. The tracedenoted “CorFlow” is a record of blood flow in the coronary artery, thetrace denoted “LVdP/dtmax” is a record of the maximum value of the1^(st) derivative of left ventricular pressure per each cardiac cycle,and the trace denoted “CO” is a recording of cardiac output as derivedfrom mean aortic flow. The record depicted in FIG. 21 begins with thefinal few seconds of a six-minute long, paced tachyarrhythmia (theportion of the traces before the “End VT” marker). This is followed byapproximately 10 seconds of normal sinus rhythm (NSR) with severehemodynamic dysfunction that could be classified as pulseless electricalactivity (PEA) or electro-mechanical dissociation (EMD). During thistime, coronary blood flow and cardiac output have not visibly increasedcompared to flows occurring during the tachyarrhythmia. Without adequateblood flow, the heart will remain ischemic and the subject will likelydie of PEA. The portion of FIG. 21 denoted by a horizontal arrow marked“RPS Therapy,” marks the period during which RPS pacing therapies weredelivered in the right ventricular apex of the heart of the subject.During this period, all measured pressures and flows are appreciablyaugmented on the very first cardiac cycle following delivery of thefirst pacing (RPS) stimuli. The values continue to increase and begin torecover to normal physiologic levels within approximately one minute. Atthe end of the RPS therapy delivery segment, there has been sufficientcoronary flow to re-perfuse the heart, allowing it to resume functionwithout additional therapy. It cannot be overemphasized that return ofspontaneous circulation in this subject occurred without anypharmacological or mechanical support therapy or treatment but insteadrelied exclusively on electrical stimulation delivered according to thepresent invention.

Recognition of the need for such therapy may depend on clinicians or anautomated device, either implanted or external, and stimulation therapyapplied transcutaneously or from electrodes on or near the heart. FIG.22, which is an annotated version of FIG. 17, contains some addedinformation regarding duration and improvement criteria, halting therapydelivery and adjustment of amplitude and timing of RPS therapy to lowerarrhythmia risk.

The start-stop rules may operate using a variety of schemes and sensorinputs as depicted in FIG. 2 which are microprocessor or hardwarecontrolled and programmable with values determined by algorithms orclinicians, such as depicted in the system diagrams of FIG. 3A and FIG.3B.

Detailed Description of Identification of Refractory and Non-RefractoryIntervals.

Turning now to FIG. 23 (A through D) which is a composite illustrationcomposed of four X-Y plots of data showing critical timing sequencesbetween such plots of data with respect to delivery of excitatory (RPS)and nonexcitatory stimulation (NES) therapy. An unlabeled time-alignedsurface representative ECG electrogram trace appears at the top of thefigures for ease of cross-reference.

In FIG. 23A, a stimulus intensity curve is depicted wherein a primarydeterminant of the timing associated with arrhythmia risk andhemodynamic benefit derived from RPS excitatory stimulation. It will beappreciated that stimulation pulses of greater amplitude than the curve(at a given moment in time) are necessary to capture and thus providebenefit from RPS stimulation therapy. An absolute refractory period isdepicted in FIG. 23A. During this period no depolarizations result andthis is ideal for nonexcitatory neurostimulation (NES) with electrodesnear the heart. In the period labeled “vulnerable period,” which occursjust outside of the absolute refractory period, very high amplitudepulses can cause arrhythmias including repetitive extrasystoles, VT, orVF. For practical purposes, excitatory stimulation pulses are deliveredsome margin above the threshold so that capture is a binary phenomenon.Stimulation pulse amplitude, however, is also maintained low so that therisk of arrhythmias is very low even when timed to coincide with thevulnerable period (for comparison see FIG. 23C, “arrhythmia inductionrisk curve”). As is well known in the literature, the magnitude of thepotentiation seen on the beat following the extrasystole (the postextrasystole beat) is a function of the extrasystole's timing—becominggreatest just before losing capture (as shown in FIG. 23B, (labeled“potentiation response” curve). The solid curve depicted in FIG. 23D(labeled “Net Benefit” curve), combines physiologic benefit fromexcitatory RPS stimulation and arrhythmia risk. It is most desirable tostimulate a little bit longer than (i.e., beyond) therefractory/nonrefractory boundary. The dashed Net Benefit curve showsthat nonexcitatory neurostimulation (NES) is best delivered on the“short side” of the refractory/nonrefractory boundary (or elseexcitation could result). The present invention includes methods to helpthe clinician or automated device find this refractory/nonrefractoryboundary and thus achieve the benefits of the intended therapies whilecontrolling risk.

Referring now to FIG. 24, which is a graphical depiction of electricaland hemodynamic detection of cardiac chamber capture. The trace labeled“1” is a ventricular electrogram (VEGM) obtained from the site ofapplication of the stimulation therapy. The trace labeled “2” is asecond electrogram that is near both right atrium and right ventricleand is away from the site of application of the pacing therapy. Thetrace labeled “3” is a surface ECG, traced “4” is a record of arterialblood pressure (ABP), trace “5” is a record of left ventricular pressure(LVP), trace “6” is a record of right ventricular pressure (RVP) andtrace “7” is a marker channel record of stimulation therapies applied tothe ventricles (Vtherapy). FIG. 24 illustrates embodiments of theconcept of the identification of whether or not a cardiac potentiationtherapy lies inside or outside the cardiac refractory period.

With respect trace 7, arrow 19 identifies a therapy is delivered to theventricle that lies inside the refractory period, arrow 20 identifies atherapy that lies outside the refractory period. With respect to trace1, arrow 8 identifies an electrogram tracing following a therapy thatshows no evidence of a resultant depolarization, confirming that thetherapy lies in the refractory period, and arrow 9 identifies anelectrogram tracing showing a cardiac depolarization following thetherapy, confirming that the therapy pulse captured, had sufficientamplitude and duration, and was outside the refractory period.

Similarly, with respect to trace 2, arrows 10 and 11 identify noncaptureand capture, respectively, from the electrogram at an auxiliaryelectrode site suitable to identify pulses inside and outside of thecardiac refractory period by the absence or presence of a ventriculardepolarization. With respect to trace 3, arrows 12 and 13 identify theabsence and presence of ventricular depolarizations on a surface ECG,respectively.

An embodiment of the invention would be to apply a detection algorithmto electrogram signals (possibly including but not limited to signaltraces 1-3) and identifying the presence or absence of an evokeddepolarization. This information is then used to identify whether thepreceding therapy was inside or outside of the cardiac refractoryperiod.

With respect to trace 4, arrow 14 points to a significantly augmentedABP wherein the arterial pulse pressure on the cardiac cycle following atherapy that lies outside the refractory period was augmented.Similarly, LVP (trace 5) and RVP (trace 6) are also augmented on thecycle following capture. Thus, FIG. 24 illustrates an embodiment of theinvention used to detect the presence of pressure, flow, acceleration,impedance change, or other favorable evidence of mechanical augmentationfollowing therapy delivery. This evidence also helps identify whether ornot the preceding therapy was delivered inside or outside of the cardiacrefractory period.

With respect to traces 5 and 6, arrows 15 and 17 indicate portions of aleft and right ventricular pressure waveform, respectively, resultingfrom stimulation therapy delivered in the cardiac refractory period. Asa result, no evidence of an extra-systole is seen following the therapy.

Again with respect to traces 5 and 6, arrows 16 and 18 are pressurewaveforms following a therapy delivered outside of the cardiacrefractory period. An extra-systole can be seen following this therapy.Another embodiment of the invention is adapted to apply a detectionalgorithm to a sensor that makes a measurement of cardiac mechanicalactivity, including but not limited to right ventricular, leftventricular or arterial pressure, dimension, or acceleration andidentifying the presence or absence of an extra systole. Thisinformation is used to identify whether the preceding therapy was insideor outside of the cardiac refractory period. Evoked R wave detectioninformation may then be used to time or trigger delivery of astimulation therapy that would cause post extra-systolic potentiation orwould be nonexcitatory for neurostimulation, or both.

FIG. 25 depicts three traces, VEGM, ECG and Vtherapy, respectively whichcan be used to determine whether or not capture has occurred byanalyzing a T wave. Trace 1 is a ventricular electrogram (VEGM) from thesite of application of the stimulation therapy, trace 2 is a surfaceECG, and trace 3 is a marker channel record of applied stimulationtherapies. With respect to trace 1 and 2, arrows 4 and 7 are electrogramsignals indicating a ventricular depolarization and arrows 5 and 8 aresignals showing a resulting ventricular repolarization or T-wave. Intrace 3, arrow 10 corresponds to a marker of the delivered therapy,which was applied just after the T-wave. In traces 1 and 2, arrows 6 and9 indicate the resultant depolarization from the applied therapy.

Another embodiment of the therapy capture aspect of this invention isused to identify the evoked T-wave from an electrogram signal followingapplication of a therapy pulse. A further embodiment is to rely directlyon the time of occurrence of the T-wave (between the depolarization andrepolarization from an electrogram signal) to form an index of theboundary between refractory (before the T-wave) and nonrefractory (afterthe T-wave) intervals. The T-wave detection information may then be usedto time or trigger delivery of a stimulation therapy that would causepost extra-systolic potentiation or would be nonexcitatory forneurostimulation, or both.

FIG. 26 is a flow chart that diagrams response to capture information toapply nonexcitatory neurostimulation (NES) therapy. Following aventricular pace or sense event, the sensing circuits remain active anda timer counts down a delay until the scheduled delivery of the NESstimulation pulse(s). If there has been no intrinsic event in thisinterval, the NES pulse(s) are delivered and electrogram or mechanicalsensor signals employed (such as described herein above) to determine ifcapture and an extrasystole occurred. If capture did occur, the deliverytime, stimulation amplitude, or pulse number is decreased and theprocess repeated. The value for Tdelay is typically 10-120 ms. Tdelayand other stimulus parameters may also be influenced by observations ofheart rate or other physiologic sensors in addition to the electricaland mechanical parameters discussed above.

FIG. 27 is a flow chart that diagrams response to capture information toapply excitatory RPS therapy. Following a ventricular pace or senseevent, the sensing circuits such as depicted in FIG. 3A and FIG. 3Bremain active and a timer counts down a delay until the scheduleddelivery of the RPS stimulation pulse(s). If there has been no intrinsicevent in this interval, the pulse(s) are delivered and electrogram ormechanical sensor signals employed (such as described herein above) todetermine if capture and an extrasystole occurred. If capture did notoccur, the delivery time, stimulation amplitude, or pulse number isincreased and the process repeated. The value for Tdelay is typically200-300 ms. Tdelay and other stimulus parameters may also be influencedby observations of heart rate or other physiologic sensors in additionto the electrical and mechanical parameters discussed above. Thisalgorithm is also used for the pulse(s) intended to produce RPS whenaccompanied by NES pulse(s).

The identification of refractory and non-refractory intervals andappropriate timing of pulses may operate using a variety of timingschemes and sensing circuits which are both preferably microprocessor orhardware controlled and programmable with input values determined byalgorithms or clinicians, such as depicted in the system diagrams ofFIG. 3A and FIG. 3B.

Detailed Description of Management of SVT with RPS Therapy.

FIG. 28 is a series of four X-Y plots (labeled A-D) illustratingdeceleration of a rapid SVT by applying RPS therapy according to oneembodiment of the present invention. Such a rapid SVT results whenectopic or reentrant rhythms involve the atria or AV node and conduct tothe ventricles (trace A). Conduction to the ventricles is so rapid as toimpair filling and ejection and as a result pressures and flows aretypically impaired (trace B). The introduction of excitatory RPSstimulation pulses (denoted Vth in trace C) creates additionalrefractory time in the ventricles and a 2:1 rate reduction takes place.Furthermore, potentiation and enhanced mechanical function results (asseen in D). The net result is an effective rate reduction with improvedhemodynamic performance. This RPS therapy regimen not only transforms apotentially life threatening SVT into a well tolerated rhythm, butallows more time for termination of the arrhythmia by natural, device,or drug means.

The deceleration of rapid SVT by RPS therapy may operate using a varietyof timing schemes and sensing circuits which are both preferablymicroprocessor or hardware controlled and programmable with input valuesdetermined by algorithms or clinicians, such as depicted in the systemdiagrams of FIG. 3A and FIG. 3B.

Detailed Description of Feedback Control.

FIG. 29 is composed of two X-Y plots illustrating basic controlrelationships for NES and RPS stimulation. In FIG. 29, the index ofcardiac mechanical function is taken to be dP/dt max as a percentage ofbaseline, although other variables such as arterial pulse pressure orcardiac output may be used. In the top X-Y plot appearing near the topof FIG. 29, the RPS potentation response is seen to be governed by thetiming of stimulation that elicits an extrasystole. It is not affectedby stimulation intensity and needs to be outside of the refractoryperiod (here shown as 0-200 ms). Non-excitatory neurostimulation,however needs to be nonexcitatory and for electrodes near the heart thismeans inside the refractory period. NES is also strongly dependent onstimulation intensity (here shown as current in mA but may also includevoltage, pulse duration or the number of multiple pulses).

FIG. 30 is composed of two X-Y plots illustrating the need to adjuststimulation parameters to maintain desired level of enhanced function.Variations across and within subjects of response to stimulation occurand can impact the resulting level of enhanced function. For both RPSpotentiation and NES neurostimulation this may take the form of shiftsin the absolute level of response (or offset) but for convenience thishas been removed by normalizing to a non-stimulated baseline in therecent past of 100%. The remaining variation takes the form of shifts inthe slope or the NES response, but for RPS takes on both changes ofslope (change of dP/dt max per unit time) as well as shifts in therefractory period where no potentiation results. As a result, astimulation time that once gave the desired level of enhancement may nowbe associated with no enhancement, more or less mechanical functionenhancement of the heart, and a different slope. In order to maintain alevel of beneficial effect on cardiac function, some sort of closed loopcontrol of stimulation is necessary.

FIG. 31 is a flow chart of depicting a means to control the level ofenhanced cardiac function. Adjustments in stimulation timing oramplitude act on the heart and associated tissues and organs and areobserved by electrical, mechanical, metabolic, or other physiologicsensors. In the most elementary situation, a clinician observes thissensor information and adjusts the stimulation accordingly. This may bethought of as closing the loop but results in a slow response time.Implantable or external device implementations of this invention mayalso close the loop more promptly by following a control algorithm in aportion of the therapy delivery device termed a controller. As with allpractical control systems, provision for manual override and tuning ofthe controller are provided. This aspect of therapy control may beconsidered separately from the start/stop and safety lockout rulesdescribed elsewhere.

FIG. 32 is a block diagram illustrating a basic PID controller forautomatic adjustment of stimulation therapy. One of the most basic ofautomatic control schemes is the PID controller depicted in FIG. 32. Atarget level (or setpoint) is compared with the actual level derivedfrom a sensor and the difference is referred to as the error. In a PIDcontroller, there is a proportional pathway with an associatedmultiplicative constant P, a pathway that integrates the error withconstant 1, and a pathway that works with the derivative of the errorwith constant D. Practical PID controllers usually implement absolutelimits to the commanded output and similarly limit the integral of error(a property called anti-windup limiting). Furthermore these controllersare also usually implemented in a fashion such that the transition frommanual or fixed output to automatic control output occurs smoothly (aproperty called bumpless transfer). In the present application, thiscontroller updates stimulation parameters once per cardiac cycle withrelatively straightforward computations and thus is not a significantburden to the processing power of implanted or external medicalinstrumentation.

FIG. 33 depicts a series of empirical measurements that illustrates theeffect of a P+I controller maintaining RPS cardiac enhancement. A P+Icontroller was employed using RV dP/dt max as the control variable andthe results are shown here. A setpoint of 700 mmHg/s was entered (whichwas significantly greater than the baseline level of 280 mmHg/s). Limitsfor the RPS therapy pulse's timing were established (here 250 to 400 mswas used) and the therapy initiated. The desired level of enhancedfunction was achieved rapidly and the mean level of RV dP/dt maxremained around the setpoint as the feedback controller continuouslyadjusted the timing (Tdelay). Incorporation of an integrator in thefeedback loop assures the mean error is zero. In this patent disclosure,the inventors report that they increased the controller gain to thepoint where oscillations developed, an instability phenomenon well knownin the area of feedback control. RPS stimulation not only decreasedheart rate from 90 to 50 bpm, but also resulted in a simultaneous andsustained increase in LV dP/dt max from about 1100 to 2600 mmHg/s. Asignificant feature of this invention is that in the process ofadjusting RPS stimulation timing to maintain a desired level of enhancedfunction, the controller automatically adapts to changes in thepotentiation response curve. This keeps the controller clear of therefractory period and in an operating region where linear feedbackcontrol applies. Similar linear feedback controllers may be applied toNES neurostimulation and combined NES and RPS stimulation. Suchcontrollers also act in concert with rules for starting and stoppingstimulation therapy and safety lockout rules as described elsewhere inthis invention.

The feedback control may operate using variations of the controllersdescribed which are preferably microprocessor or hardware controlled andprogrammable by algorithms or clinicians, such as depicted in the systemdiagrams of FIG. 3A and FIG. 3B.

Detailed Description of Extensions to Tachyarrhythmia ManagementDevices.

FIG. 34 is a flow chart depicting a technique for extending usual shockalgorithms for ICDs and AEDs to facilitate NES and/or RPS therapy.Another important aspect of this invention is the recognition thatcertain seriously compromised states formerly believed almost uniformlyfatal such as EMD or PEA, may in fact respond to electrical stimulationtherapy. Present generation ICD and AED devices may then be altered toreflect this possibility. This flow chart illustrates some significantchanges. First, it introduces the RPS, NES, or combined stimulationtherapies described elsewhere in this invention into the device'salgorithm by checking for the presence of severe hemodynamic dysfunctionafter tachyarrhythmia termination and applying therapies. Then, if morethan a set number of shocks (n) are delivered in a single episode orcluster of episodes, more time consuming and accurate VF detection rulesare instituted to reduce the risk inadvertently shocking rhythms that donot respond to shocks while still maintaining the capability torecognize and treat VF. The potential negative impact of slower VFdetection is now balanced by less risk of inadvertent shocks and animplementation of stimulation therapy to assist in recovery of longerduration tachyarrhythmias. Finally, the flow chart introduces a furtheranalysis of surface ECG or intracardiac electrogram signals or othersensors following an extended but unsuccessful effort to end thetachycardia. The device or the device and clinician look for featuresthat are associated with an improved success rate for tachyarrhythmiaconversion such as fine VF. Although current thinking is that thesurvival rate when responding to shocks or ATP therapies this late intoa tachycardia episode is too poor to warrant therapies, the stimulationtherapy invention described herein appears to have opened the door tofurther life saving and life sustaining therapies.

An additional aspect of the present invention is to modify existingrhythm recognition algorithms of implanted and external therapy devicesto accommodate operating concurrently with therapy pulses delivered by apreexisting external or implanted device respectively. The sharp changesin electrogram slew rate associated with stimulation pulses may berecognized and ignored for the purpose of automated rhythm recognition.Further, closely coupled pairs of ventricular depolarizations withstimulation pulses detected shortly before the second depolarization, inthe setting of cardiac dysfunction, are presumed to be RPS extrasystolesand not an intrinsic bigeminal tachycardia rhythm. The devices analyzethe effective heart rate and rhythm accordingly and do not falselydetect or treat tachyarrhythmias.

Diagram of Integrated RPS, NES, Defibrillation and Pacing Concepts

FIG. 35 is a flowchart illustrating significant aspects of stimulationtherapies according to some aspects of the present invention describedherein. Various components of this invention work together to providesafe and effective stimulation therapies for cardiac dysfunction,including arrhythmias and HF, among others. Beginning with the upperleft portion of FIG. 35, block 4 incorporates the rules by which therapyas a whole is initiated or terminated, thus this aspect (block 4)encloses the others in the dotted border. This aspect may be anautomated algorithm or may require input from a clinician or thepatient. Block 6 depicts the closed loop feedback controller thatgathers a measure of cardiac function from the mechanical sensors and adesired control point from the clinician or patient. The controllerdepicted as block 6 then adjusts the timing or the amplitude of thetherapy to achieve this desired control point. Block 5 includes thealgorithms used to identify the refractory period of the heart whichuses as an input either electrical sensing of cardiac depolarizations orrepolarizations or mechanical sensing of extra-systoles or potentiation.If non-excitatory neurostimulation (NES) is desired, the algorithm keepsthe therapy timing within the refractory period. In the case of RPSstimulation, the refractory period is avoided. Block 5 can also beviewed as a range limiting system, it limits the range of therapytimings that it receives from the feedback controller. Block 3 includesthe algorithms that lock out therapy if an abnormal cardiac event suchas a premature ventricular contraction or a tachyarrhythmia occurs.Block 1 is the dual-chamber pacing engine of the device, incorporatingfull dual chamber sensing/pacing capability with the added functionalityof atrial coordinated pacing (ACP) with RPS therapies. Finally, block 7is a defibrillation system including detection of tachyarrhythmic eventsand application of either shock or pacing therapies such as ATP toterminate these events. The system also includes new rules to increasesurvivability of long duration episodes of tachycardia or dysfunctionnormally associated with high-mortality.

While the various components depicted in FIG. 35 preferably areintegrated into a single medical device not all such components must beincluded in any particular medical device. In fact, the components maybe distributed between remote devices and coupled wirelessly orotherwise to perform according to the foregoing description. Medicaldevices employing such components may comprise IMDs, AED or otherexternal medical devices, device programmers, temporarypacing/defibrillation devices and the like.

FIG. 36 is a diagram illustrating an embodiment of the present inventionembodied into a conventional AED device. In one form of this embodiment,such a conventional AED has a cardiac pacing system adapted for TCP(such as pace/sense circuit 32). While not depicted, the user interfacewould be reconfigured to display appropriate pacing and sensingindicators and enhanced microprocessor capability to handle TCP.

In another form of this embodiment, a conventional AED is configured forRPS and/or NES therapy delivery according to the present invention.Suitable AED circuitry for delivery of RPS and/or NES therapy may belocated within pace/sense circuit 32. While not depicted, the userinterface would be reconfigured to display appropriate pacing andsensing indicators and enhanced microprocessor capability to handle RPSand NES therapy. This form of the invention is preferably based almostexclusively upon electrical signals derived from surface electrodes.

In yet form of this embodiment, an AED would beneficially includevarious physiologic sensors to better assess the degree of cardiacdysfunction and response to delivered therapies (e.g., defibrillation,RPS, NES, TCP and the like). As depicted in FIG. 36 one or more sensors1,2,3 may be coupled to the AED to assess the need and efficacy oftherapy. Examples of such sensors include a pulse oximeter 1, anon-invasive blood pressure sensor 2, a capnometer (i.e., an expired CO₂sensor) 3 and the like. In combination with such sensors signalconditioning circuitry 4,5,8 are preferably coupled to amplify andfilter such signals and make them available to the microprocessor andrelated circuitry of the AED.

One significant advantage of all forms of this embodiment that includeRPS results from the fact that conventional AED defibrillationfrequently immediately terminates a lethal rhythm but often fails torestore adequate cardiac function. As a result, a victim of suddencardiac arrest oftentimes rapidly or eventually succumbs to cardiacdysfunction or EMD/PEA. An AED configured to deliver RPS therapypromptly following termination of the tachyarrhythmia beneficiallyattempts to restore adequate cardiac function. Prompt restoration ofcardiac mechanical function is exceptionally critical immediatelyfollowing termination of such a potentially lethal tachyarrhythmia andis provided by this aspect of the present invention.

The following examples are intended as illustrative and are not intendedto be limiting of the scope of the claimed invention.

EXAMPLE 1 AED Example with Presentation of VF

Despite the increasing availability to quick access defibrillation bythe public and quickening response times, the prognosis of a victim of asudden cardiac arrest surviving to a hospital discharge is low, withmany of these victims succumbing to electromechanical dissociation (EMD)or pulseless electrical activity (PEA). Current AED technology isequipped to treat tachyarrhythmias but has no means to treat EMD/PEA.

An AED equipped with the features detailed in this invention wouldaddress these scenarios. In an example implementation, the AED wouldappear identical to the first responder. The responder would place twotransthoracic self-adhesive electrodes on the patient and depress astart button on the device. The AED would then obtain a surface ECG fromthe transthoracic electrodes and apply a VF detection algorithm to thesignal. If VF was detected, the AED would apply a defibrillation shockand then apply a re-detection algorithm. If VF stopped or was neverpresent, the device would check to see if the patient was in abradyarrhythmia or asystole and then would apply pacing therapiesthrough the transthoracic electrodes if needed. Furthermore, uponsensing a sinus rhythm or during a paced rhythm, the device wouldrequest for the responder to obtain a pulse from the victim. If a pulsewas not detected, the responder would press a button on the AED, whichwould initiate RPS/NES therapies, delivered through the transthoracicelectrodes. The device would periodically request additional pulsechecks and would have an abort button clearly labeled, allowing theresponder to terminate therapy should the victim regain consciousness.

Alternatively, the AED would be connected to a sensor that made anon-invasive measurement of cardiac function such as a pulse oximeter ora non-invasive blood pressure device such as a inflatable arm cuff. Sucha system would not require the responder to make assessments of thevictims pulse and would automatically start and stop RPS/NES therapy asneeded.

EXAMPLE 2 ICD Example with Presentation of VT

ICD systems provides patients with greatly improved survivability fromepisodes of sudden cardiac arrest when compared to patients treated withAED's mainly because there is minimal time to wait between the onset ofthe arrhythmia and delivery of therapy when the device is implanted andalways ready to detect events. However, some patients, especially thosewith more pronounced HF, may not tolerate well even the shortest of VFepisodes and may have depressed cardiac function long after thearrhythmia is terminated. Additionally, circumstances may arise thatlengthen the duration of the tachyarrhythmia before the device deliversa therapy. Some tachyarrhythmias pose detection problems for ICD's,which may postpone delivery of therapy. An arrhythmia could also requireseveral shocks to terminate, further prolonging the episode.

During a tachyarrhythmia, the coronary blood flow perfusing the heartcan become severely impaired, leading to ischemia and a temporary lossin cardiac contractility referred to as stunning. If the loss incontractility is severe enough to prevent restoration of coronary flowonce the arrhythmia is terminated, further ischemia will result, leadingto further diminishment of contractility in a downward spiral. A therapyto quickly restore contractility can break this cycle and lead torestoration of sustained cardiac function.

An example of a RPS/NES stimulation therapy would include treatingimpaired cardiac mechanical function following a tachyarrhythmia. In anexample scenario, an ICD equipped with such a therapy would log theduration of any detected tachyarrhythmia. If the duration of the episodeexceeded a programmable threshold before being terminated, indicatingthat the likelihood was high that cardiac mechanical function wasseverely impaired, the device would initiate a NES/RPS therapy for afixed duration following the episode to provide a quick boost inhemodynamics to hasten re-perfusion of the heart and allow a morecomplete recovery from the tachyarrhythmia. Alternatively, an RVpressure sensor could detect RV pulse pressure following the episode andcompare it to a baseline value measured and stored before the episodewas detected. Should the RV pulse pressure fall shy of the baselinevalue for too great of a time following the tachyarrhythmia, indicatingprolonged periods of depressed cardiac mechanical function, the ICDwould initiate RPS/NES therapies and then terminate the therapies afterthe RV pressure reached some percentage of the baseline measurement,indicating that the cardiac function was restored.

EXAMPLE 3 HF Example with Presentation of Acute Decompensation

Advanced stage HF patients experience sudden worsening of heart failureassociated symptoms which require hospitalization. The transition fromchronic compensated HF to acute decompensated HF may result from anumber of factors including dietary indiscretion, progress of HFdisease, and acute myocardial infarction. When severe, symptoms mayprogress in a few hours to a stage where these patients need to beadmitted to a critical care hospital bed, monitored by physiologicsensors, and treated with a variety of drugs including intravenousinotropes. A patient experiencing such a decompensation commonlyexhibits low cardiac output at rest, poor contractile function and lowdP/dt max, slow relaxation and high tau, elevated diastolic ventricularpressures, and reduced ventricular developed pressures.

Cardiac resynchronization therapy delivered by an implanted device is animportant adjunct to good medical therapy. Such a resynchronizationdevice possesses electrodes and circuitry suited to deliver NES and/orRPS stimulation therapy. Implantable monitoring technology tocontinuously monitor cardiac performance using RV pressure is undergoingclinical trials. In this scenario, the implantable device is equipped toprovide stimulation therapies and monitor hemodynamic function as taughtby this invention.

Upon detection of a rise of RV diastolic pressure and decreasedcontractility assessed by dP/dt from a mean value established over thepast 2-4 weeks, RPS therapy may be initiated with a single 2.0 V, 0.5 msventricular pulse delivered 260 ms after a Vsense event from a RV apexbipolar lead. At this point the patient may only experience a mildworsening of HF symptoms.

In this scenario, the response to this therapy is an almost immediatedoubling of dP/dt max, increased stroke volume and ejection fraction,increased cardiac output, and reduced heart rate. Over the course of afew hours, the improved hemodynamics allow the kidneys to remove excesssalt and water and RV diastolic pressure falls back to baseline levels.Stimulation therapy is painless and automatically started anddiscontinued without being noticed by the patient. Interrogation of theimplanted device's memory reveals the episode described above and iscredited with preventing hospitalization or an emergency departmentvisit.

EXAMPLE 4 SVT Example with Poor Toleration of High Rate

Supraventricular tachycardias that result in rapid ventricular rates maybe poorly tolerated, particularly in patients with a history of heartfailure. In this scenario the patient experiences first symptoms ofdizziness and palpitations (a sensation of a fluttering within thechest). Upon evaluation by emergency medical personnel, the heart rateis found to be 220 bpm. Over the next few minutes, the patient's bloodpressure drops, and the patient becomes pale, sweaty and confused. AnAED device instrumented with NES and RPS therapies as described in thisinvention is attached to the patient by a pair of adhesive padelectrodes.

The fast but narrow ECG complexes allow the device to diagnose a seriousSVT and the operator is presented with the option of a trial of RPSstimulation or cardioversion. After administering a sedative/analgesic,a 5 minute trial of RPS stimulation is begun by delivering 20 ms pulsesof 60 mA timed 250 ms after surface ECG ventricular sense events. Vitalsigns, evaluated by the emergency personnel document that heart ratedrops from 220 to 110 bpm and that blood pressure increases from 90/50to 120/60. The patient becomes more lucid and notably more pink. Beforethe 2 minute trial is completed, the rhythm spontaneously converts to asinus rhythm at 120 bpm. The AED recognizes this and ends itsstimulation therapy immediately.

A patient with a history of HF may not tolerate a tachyarrhythmia wellfor more than a few minutes. If the rate is high enough, patients oftenloose consciousness and their rhythms deteriorate into VF. Despiteprompt and good care, defibrillation after a prolonged several minutesof cardiac ischemia may result in EMD/PEA or asystole and death. Thispatient was indicated for urgent pharmacologic or electricalcardioversion shock therapy and avoided both.

While the foregoing has been described as employing RPS alone (withincidental NES therapy due to the location of the surface electrode andmagnitude of the stimulation), it may be desirable to intentionallyinvoke NES alone or in combination with RPS therapy. This may beadvantageously employed by using one or more dedicated electrodes.

The above-described methods and apparatus are believed to be ofparticular benefit for patient's suffering heart failure includingcardiac dysfunction, chronic HF, and the like and all variants asdescribed herein and including those known to those of skill in the artto which the invention is directed. It will understood that the presentinvention offers the possibility of monitoring and therapy of a widevariety of acute and chronic cardiac dysfunctions. The current inventionprovides a system and method for delivering therapy for cardiachemodynamic dysfunction, which without limitation, may include one ofthe following features:

Therapy for cardiac dysfunction that might otherwise require inotropicdrugs such as dobutamine, calcium, or milrinone;

Therapy for cardiac dysfunction that might otherwise require mechanicalaids such as intra-aortic balloon pumps, cardiac compression devices, orLV assist device pumps;

An implantable or external device that continuously monitors thepatient, automatically administering therapy when physiologic sensorsindicate need or the patient experiences symptoms;

Treatment for cardiac dysfunction as a result of drug overdose orhypothermia;

Combined with negative inotrope drug treatments such as beta blockers toimprove patient tolerance of these treatments;

Therapy for post ischemic cardiac dysfunction or stunning such asfollowing coronary vessel occlusion, thrombolytic drugs, angioplasty, orcardiac bypass surgery;

Support for the dysfunction that is associated with coming off cardiacbypass and the use of cardioplegia;

Therapy for rapid and poorly tolerated supra-ventricular tachycardias(SVT) by regularizing 2:1 AV block, lowering mechanical heart rate andimproving mechanical function, and may facilitate arrhythmiatermination;

Management of dysfunction following tachycardic events including AT, AF,SVT, VT, or VF including elective cardioversion and urgentdefibrillation and resuscitation;

Severe bouts of heart failure, worsening to cardiogenic shock,electromechanical dissociation (EMD) or pulseless electrical activity(PEA)

Acute deterioration of cardiac function associated with hypoxia ormetabolic disorders;

Intermittent therapy for HF such as prior or during exertion or forworsening symptoms;

Continuous therapy for HF to modify heart rate, improve filling andmechanical efficiency, and facilitate reverse remodeling and otherrecovery processes;

Scheduled therapy for HF including use for a specified interval of timeat a particular time of day or scheduled delivery every N cardiaccycles;

Atrial RPS therapy to increase atrial contractility, facilitate betterventricular filling, and AV synchrony; and/or

Reducing AF burden as a result of reduced atrial loading and betterventricular function during therapy.

Consequently, the expression “heart failure” as used in above and in thefollowing claims shall be understood to embrace each of the foregoingand conditions related thereto. All patents and other publicationsidentified above are incorporated herein by reference.

While the present invention has been illustrated and described withparticularity in terms of preferred embodiments, it should be understoodthat no limitation of the scope of the invention is intended thereby.The scope of the invention is defined only by the claims appendedhereto. It should also be understood that variations of the particularembodiments described herein incorporating the principles of the presentinvention will occur to those of ordinary skill in the art and yet bewithin the scope of the appended claims.

1. A method of safely delivering neurological therapy to an innervatedmyocardial substrate of a patient to improve cardiac performance via theinnervated myocardial substrate of the ventricle, comprising the stepof: delivering electrical stimulation to at least one ventricularchamber of a heart during a refractory period of said chamber whereinsaid electrical stimulation impinges upon nerve fibers embedded in themyocardial substrate of the chamber and fails to evoke a depolarizationresponse from myocytes present in the myocardial substrate.
 2. A methodaccording to claim 1, wherein said electrical stimulation is deliveredto at least two spaced apart sites of said ventricle.
 3. A methodaccording to claim 1, wherein said electrical stimulation comprises atleast three pulses of electrical stimulation.
 4. A method according toclaim 1, wherein the electrical stimulation comprises a monophasic pulsehaving a pulse amplitude of between about five volts and 10 voltsdelivered at a frequency of between about 30 Hz and 70 Hz and whereinsaid pulse has a pulse width of between about one millisecond (ms) andabout 3 ms.
 5. A method according to claim 1, further comprising thestep of ceasing delivery of the electrical stimulation and reducing ablanking period for at least one sensing amplifiers.
 6. A methodaccording to claim 5, further comprising: determining whether anarrhythmia is present, and if not resuming the electrical stimulation.7. A method according to claim 2, wherein the spaced apart sitescomprise a first location within a coronary vein associated with a leftventricle and a right heart location.
 8. A method according to claim 7,wherein the right ventricular location comprises one of a superior venacava location and a right ventricular location.
 9. A method according toclaim 8, wherein the right ventricular location includes a right apicallocation and a right septal location.
 10. A method according to claim 6,further comprising: delivering additional electrical stimulation to aportion of non-cardiac tissue, and wherein the non-cardiac tissuecomprises at least one of the following: a portion of vagal nerve, aportion of spinal cord nerve, a location proximate an autonomic nerve sothat norephinephrine is released from said autonomic nerve in responseto the delivered at least one non-excitatory stimulation pulse, aportion of subcutaneous tissue of said patient, a portion of epidermisof said patient.
 11. A method according to claim 10, wherein saidadditional electrical stimulation is delivered from a dedicatedimplantable device separate from that which produced the electricalstimulation.
 12. A method according to claim 11, further comprising,upon delivery of the additional electrical stimulation performing oneof: ceasing delivery of the electrical stimulation, and ceasingdetermining whether an arrhythmia is present.
 13. A method of therapydelivery involving stimulation of a portion of a sympathetic nervoussystem of a patient for enhanced cardiac function, without stimulatingthe cardiac tissue sufficiently to evoke a depolarization of saidcardiac tissue, comprising the step of: delivering non-excitatoryelectrical stimulation to at least a portion of a sympathetic nervedisposed in at least a one of the following regions: a neck region, achest region, a mediastimum region, a heart region of a patient so thatsaid heart experiences improved mechanical function due at least in partto release of catecholamine substances.
 14. A method according to claim13, wherein said portion of the sympathetic nerve is at least a one ofthe following: an ansa subclavia; a portion of a thoracic sympatheticnerve; a cardiac plexus; at least a portion of a one of an unnamed setof cardiac nerves disposed alongside a coronary vessel; a portion of aninferior cervical cardiac nerve.
 15. A method according to claim 13,wherein said non-excitatory electrical stimulation comprises at lestthree discrete pulses and said pulses consist of pulsing havingapproximately 8 volts of amplitude delivered for approximately 1.5milliseconds (ms) at approximately 50 Hz.
 16. A method according toclaim 15, wherein said non-excitatory electrical stimulation isdelivered for a fraction of a temporal period.
 17. A method according toclaim 16, wherein said non-excitatory electrical stimulation isdelivered at least approximately one hour out of six hours.
 18. A methodof safely applying RPS stimulation pulse therapy to a chamber of aheart, comprising the steps of: confirming that no arrhythmia isoccurring for a predetermined number of cardiac cycles of a heart;delivering a RPS stimulation therapy to a chamber of the heart; andceasing delivery of said RPS therapy upon detection of an arrhythmia.19. A method according to claim 18, wherein after ceasing delivery ofsaid RPS therapy, further comprising the step of: implementing a non-RPStherapy to a chamber of the heart.
 20. A method according to claim 18,wherein the RPS therapy comprises: a plurality of pulses delivered atabout 8 volts of amplitude, each pulse having a pulse width ofapproximately 1.5 milliseconds (ms) at approximately 50 Hz, and whereinthe pulses are monophasic pulses.